G2Cdb::Human Disease report

Disease id
D00000305
Name
Noonan syndrome
Nervous system disease
no

Genes (3)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00000036 NF1
neurofibromin 1
Y (8317503) Insertion (I) Y
G00000031 HRAS
v-Ha-ras Harvey rat sarcoma viral oncogene homolog
Y (17054105) Microinsertion (MI) N
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (11704759) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (11992261) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12161469) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12325025) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12529711) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12717436) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12717436) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12717436) Trinucleotide substitution (TriNS) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (14974085) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15001945) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15211660) Deletion (D) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15240615) Deletion (D) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15240615) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15384080) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15539800) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15539800) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15886577) Unknown (?) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15889278) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15928039) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15929108) Unknown (?) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (16078230) Duplication (Du) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (16188759) Unknown (?) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (16498234) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (16804314) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (17020470) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (17052965) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (17184563) Unknown (?) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (17339163) Microinsertion (MI) Y

References

  • Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.

    Zampino G, Pantaleoni F, Carta C, Cobellis G, Vasta I, Neri C, Pogna EA, De Feo E, Delogu A, Sarkozy A, Atzeri F, Selicorni A, Rauen KA, Cytrynbaum CS, Weksberg R, Dallapiccola B, Ballabio A, Gelb BD, Neri G and Tartaglia M

    Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.

    Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.

    Funded by: NHLBI NIH HHS: HL71207; NICHD NIH HHS: HD01294, HD048502; Telethon: GGP04172

    Human mutation 2007;28;3;265-72

  • Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome.

    Hung CS, Lin JL, Lee YJ, Lin SP, Chao MC and Lo FS

    Division of Pediatric Endocrinology, Chang Gung Children's Hospital, Taoyuan, Taiwan.

    Noonan syndrome (NS) is an autosomal dominant disorder presenting with characteristic facies, short stature, skeletal anomalies, and congenital heart defects. Mutations in protein-tyrosine phosphatase, nonreceptor-type 11 (PTPN11), encoding SHP-2, account for 33-50% of NS. This study screened for mutations in the PTPN11 gene in 34 Taiwanese patients with NS. Mutation analysis of the 15 coding exons and exon/intron boundaries was performed by polymerase chain reaction and direct sequencing of the PTPN11 gene. We identified 10 different missense mutations in 13 (38%) patients, including a novel missense mutation (855T>G, F285L). These mutations were clustered in exon 3 (n = 6) encoding the N-SH2 domain, exon 4 (n = 2) encoding the C-SH2 domain, and in exons 8 (n = 2) and 13 (n = 3) encoding the PTP domain. In conclusion, this study provides further support that PTPN11 mutations are responsible for Noonan syndrome in Taiwanese patients.

    Journal of the Formosan Medical Association = Taiwan yi zhi 2007;106;2;169-72

  • Severe aortic valvar stenosis in familial Noonan syndrome with mutation of the PTPN11 gene.

    Abadir S, Edouard T and Julia S

    Department of Pediatric Cardiology, Hôpital des Enfants, Toulouse, France. abadir@club-internet.fr

    Noonan's syndrome is an autosomal dominant genetic disease, in which mutation of the PTPN11 gene is found in from one-third to half of all cases. Pulmonary valvar stenosis and myocardiopathy are frequently associated cardiac malformations, whereas aortic valvar stenosis is rarely described. We report, as far as we know, the first case of familial Noonan syndrome with severe aortic valvar stenosis, demonstrating mutation of the PTPN11 gene in the father of the patient.

    Cardiology in the young 2007;17;1;95-7

  • Mild variable Noonan syndrome in a family with a novel PTPN11 mutation.

    Zenker M, Voss E and Reis A

    Institute of Human Genetics, University of Erlangen--Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany. mzenker@humgenet.uni-erlangen.de

    Noonan syndrome (OMIM 163950) is a common genetic condition with variable clinical expression and genetic heterogeneity. About half of the cases can be accounted to activating mutations in the PTPN11 gene encoding SHP-2. We report on a family with mild, variable expression of Noonan syndrome in five individuals. Clinical manifestations included short stature, craniofacial anomalies and thorax deformity, but none of the affected family members had a heart defect. Sequencing of the entire coding region of PTPN11 revealed a novel mutation c.1226G-->C in exon 11 predicting the amino acid exchange G409A. This mutation is not located in the previously known mutation clusters. Our observation and the recent report of a mutation affecting a neighbouring residue (T411M) in a family with a variable phenotype suggest that mutations in this particular region of SHP-2 may have effects on the protein that differ from those of the classical mutations.

    European journal of medical genetics 2007;50;1;43-7

  • Therapy-related acute myeloid leukemia in a child with Noonan syndrome and clonal duplication of the germline PTPN11 mutation.

    Chantrain CF, Jijon P, De Raedt T, Vermylen C, Poirel HA, Legius E and Brichard B

    Department of Pediatric Hematology-Oncology, St-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium. christophe.chantrain@pedi.ucl.ac.be

    A 4-year-old girl with Noonan syndrome (NS) and constitutive PTPN11 mutation presented with stage 4 neuroblastoma and was treated by intensive chemotherapy. During the treatment, cytogenetic analysis revealed the development of a hyperdiploid clone with duplication of the germline PTPN11 mutation in a morphologically normal bone marrow. A few months later, the patient developed acute myelomonoblastic leukemia with an additional clonal deletion of 7q. Although, we cannot conclude whether there is an association between NS and neuroblastoma, this case suggests that duplication of germline PTPN11 mutations, potentially induced by chemotherapy, contributes to leukemogenesis in patients with NS.

    Pediatric blood & cancer 2007;48;1;101-4

  • A PTPN11 gene mutation (Y63C) causing Noonan syndrome is not associated with short stature in general population.

    Takahashi I, Utsunomiya M, Inoue K, Takahashi T, Nozaki J, Wada Y, Takada G and Koizumi A

    Department of Pediatrics, Akita University School of Medicine, Japan. tomy@med.akita-u.ac.jp

    Human growth is a highly complicated process, but it is obviously influenced by a genetic factor. Recent genome-wide linkage analyses suggested some genetic regions underlying stature variations. However, any specific genes underlying stature variations have not been identified. Noonan syndrome (NS) is an autosomal dominant disorder clinically characterized by short stature, minor facial anomalies, and congenital heart defects. Recently, PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) has been identified as a major responsible gene for NS, causing about half of the affected individuals. We herein report a large family demonstrating NS caused by one of the common PTPN11 mutations, c.188 A > G (Y63C). In this family, the patients were apparently healthy, but heterozygosity of the c.188 A > G (Y63C) mutation was related to growth impairment. This finding suggested that PTPN11 genetic variants contribute to adult height in the general population. However, c.188 A > G (Y63C) was not identified in 96 short individuals from the general population of 2,281 healthy adults. Thus, it is unlikely that PTPN11 is one of the genes underlying stature variations in the general population.

    The Tohoku journal of experimental medicine 2006;208;3;255-9

  • Does the rare A172G mutation of PTPN11 gene convey a mild Noonan syndrome phenotype?

    Kitsiou-Tzeli S, Papadopoulou A, Kanaka-Gantenbein C, Fretzayas A, Daskalopoulos D, Kanavakis E and Nicolaidou P

    Department of Medical Genetics, University of Athens, Aghia Sophia Children's Hospital, Thivon & Levadias, Goudi, Athens, Greece. skitsiou@uoa.med.gr

    Background: Noonan syndrome NS (OMIM 163950) is an autosomal dominant developmental disorder characterized mainly by typical facial dysmorphism, growth retardation and variable congenital heart defects. In unrelated individuals with sporadic or familial NS, heterozygous missense point mutations in the gene PTPN11 (OMIM 176876) have been confirmed, with a clustering of mutations in exons 3 and 8, the mutation A922G Asn308Asp accounting for nearly 25% of cases.

    We report a 7-year-old boy with short stature and some other clinical features of NS, who has been investigated by molecular analysis for the presence of mutations in the PTPN11 gene.

    Result: The de novo mutation A172G in the exon 3 of the PTPN11 gene, predicting an Asn58Asp substitution, has been found. To the best of our knowledge, this specific mutation has only been described once before, but this is the first report of detailed clinical data suggesting a mild phenotype.

    Conclusion: Detailed clinical phenotype in every patient with major or minor features of NS and molecular identification of PTPN11 gene mutation may contribute to a better phenotype-genotype correlation.

    Hormone research 2006;66;3;124-31

  • PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype.

    Bertola DR, Pereira AC, Albano LM, De Oliveira PS, Kim CA and Krieger JE

    Clinical Genetics Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil. deborarb@icr.hcnet.usp.br

    Mutations in the PTPN11 gene are known to cause a large fraction of the cases of Noonan syndrome. The objective of this study was to determine the PTPN11 gene mutation rate in a cohort of clinically well-characterized Brazilian patients with Noonan or Noonan-like syndromes and to study the genotype-phenotype correlation. Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 5 with Noonan-like/multiple giant cell lesion syndrome, and 3 with neurofibromatosis/ Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography (DHPLC) followed by sequencing of amplicons with an aberrant elution profile. We detected missense mutations in the PTPN11 gene in 21 probands with Noonan syndrome (42%), in all 3 patients with LEOPARD syndrome, and in 1 case with Noonan-like/multiple giant cell lesion syndrome. One patient with neurofibromatosis-Noonan syndrome had a mutation in both the PTPN11 and NF1 genes. The only anomalies that reached statistical significance when comparing probands with and without mutations were the hematological abnormalities. Our data confirms that Noonan syndrome is a genetically heterogeneous disorder, with mutations in the PTPN11 gene responsible for roughly 50% of the cases. A definitive genotype-phenotype correlation has not been established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, mutation of the PTPN11 gene is the main causal factor in LEOPARD syndrome, and it also plays a role in neurofibromatosis-Noonan syndrome. Noonan- like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous.

    Genetic testing 2006;10;3;186-91

  • The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.

    Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergsträsser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, Stary J, Trebo M, Zecca M, Gelb BD, Tartaglia M and Loh ML

    University of California, Room HSE-302 Box 0519, San Francisco, CA 94143, USA.

    Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n = 107); (2) patients with NS/MPD (n = 19); and (3) patients with NS (n = 243). Glu76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) being most frequent. Eight of 19 patients with NS/MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS/MPD and JMML.

    Funded by: NCI NIH HHS: K24 CA80916, P30 CA82103, R01 CA104282, R01 CA95621; NHLBI NIH HHS: HL074728, HL71207; NICHD NIH HHS: HD01294; Telethon: GGP04172

    Blood 2005;106;6;2183-5

  • A novel mutation in the PTPN11 gene in a patient with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy.

    Takahashi K, Kogaki S, Kurotobi S, Nasuno S, Ohta M, Okabe H, Wada K, Sakai N, Taniike M and Ozono K

    Department of Developmental Medicine (Paediatrics), Osaka University Graduate School of Medicine, 2-2 Yamada-oka, 565-0871 Suita, Osaka, Japan.

    Unlabelled: A male infant with clinical features of Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy is reported. He manifested severe heart failure and failure to thrive. Administration of propranolol and cibenzoline improved ventricular outflow tract obstruction, leading to catch-up growth. Genetic analysis of the patient revealed a novel missense mutation in the PTPN11 gene.

    Conclusion: This is the first description of a patient with a Gln510Glu mutation in the protein-tyrosine phosphatase, non-receptor type 11 gene. This specific mutation may be associated with a rapidly progressive hypertrophic cardiomyopathy.

    European journal of pediatrics 2005;164;8;497-500

  • Acute myeloid leukemia in an adult Noonan syndrome patient with PTPN11 mutation.

    Matsubara K, Yabe H, Ogata T, Yoshida R and Fukaya T

    American journal of hematology 2005;79;2;171-2

  • A new PTPN11 mutation in juvenile myelomonocytic leukaemia associated with Noonan syndrome.

    Giovannini L, Cavé H, Ferrero-Vacher C, Boutte P and Sirvent N

    Acta paediatrica (Oslo, Norway : 1992) 2005;94;5;636-7

  • [Noonan syndrome and Leopard syndrome linked to mutation of the gene PTPN11].

    Dereure O

    Service de Dermatologie, Hôpital Saint-Eloi, 80, avenue Augustin Fliche, 34295 Montpellier Cedex 5.

    Annales de dermatologie et de venereologie 2005;132;4;400

  • Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation.

    Bertola DR, Pereira AC, de Oliveira PS, Kim CA and Krieger JE

    Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, 05403-900 São Paulo, Brazil. drbetola@attglobal.net

    Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30-50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with downslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene-gene or gene-environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first-degree relatives should also be tested for the specific mutation.

    American journal of medical genetics. Part A 2004;130A;4;378-83

  • A 3-bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia.

    Yoshida R, Miyata M, Nagai T, Yamazaki T and Ogata T

    Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya, Tokyo 154-8567, Japan.

    A de novo 3-bp deletion (179-181delGTG) was identified at exon 3 of the PTPN11 gene in a female infant with severe Noonan phenotype including hydrops fetalis and juvenile myelomonocytic leukemia. Since the 3-bp deletion is predicted to result in loss of the 60th glycine in the N-SH2 domain that is directly involved in the intramolecular interaction between the N-SH2 and the PTP domains of the PTPN11 protein, this mutation would disrupt the N-SH2/PTP binding in the absence of a phosphopeptide, leading to an excessive phosphatase activity. The results expand the spectrum of PTPN11 mutations in Noonan syndrome (NS), and suggest that a PTPN11 mutation leads to a wide range of clinical features of Noonan syndrome.

    American journal of medical genetics. Part A 2004;128A;1;63-6

  • Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.

    Yoshida R, Hasegawa T, Hasegawa Y, Nagai T, Kinoshita E, Tanaka Y, Kanegane H, Ohyama K, Onishi T, Hanew K, Okuyama T, Horikawa R, Tanaka T and Ogata T

    Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan.

    We report on PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutation analysis and clinical assessment in 45 patients with Noonan syndrome. Sequence analysis was performed for all of the coding exons 1-15 of PTPN11, revealing a novel 3-bp deletion mutation and 10 recurrent missense mutations in 18 patients. Clinical assessment showed that 1) the growth pattern was similar in mutation-positive and mutation-negative patients, with no significant difference in birth length [-0.6 +/- 2.2 sd (n = 10) vs. -0.6 +/- 1.4 sd (n = 21); P = 0.95], childhood height [-2.6 +/- 1.1 sd (n = 14) vs. -2.1 +/- 1.6 sd (n = 23); P = 0.28], or target height [-0.4 +/- 0.9 sd (n = 14) vs. -0.2 +/- 0.7 sd (n = 17); P = 0.52]; 2) pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients (10 of 18 vs. 6 of 27; P = 0.02), as was atrial septal defect (10 of 18 vs. 4 of 27; P = 0.005), whereas hypertrophic cardiomyopathy was present in five mutation-negative patients only; and 3) other features were grossly similar in the prevalence between mutation-positive and mutation-negative patients, but hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, were exclusively present in mutation-positive patients (5 of 18 vs. 0 of 27; P = 0.007). The results suggest that PTPN11 mutations account for approximately 40% of Noonan syndrome patients, as has been reported previously. Furthermore, assessment of clinical features, in conjunction with data reported previously, implies that the type of cardiovascular lesions and the occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients, whereas the remaining findings are similar in the two groups of patients.

    The Journal of clinical endocrinology and metabolism 2004;89;7;3359-64

  • Genotype-phenotype correlations in Noonan syndrome.

    Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A and Rauch A

    Institute of Human Genetics, Departments of Pediatric Endocrinology and Pediatric Cardiology, University Children's Hospital, Erlangen, Germany.

    Objective: To study genotype-phenotype correlations in a cohort of clinically well-characterized pediatric patients with Noonan syndrome (NS). Study design Fifty-seven unrelated patients with the clinical diagnosis of NS ascertained according to standardized inclusion criteria were prospectively enrolled. Mutational analysis was performed by direct sequencing of the entire coding sequence of the PTPN11 gene.

    Results: Sixteen known and 3 novel PTPN11 mutations could be detected in 60% of index patients, in all familial and in 52% of the sporadic cases. Presence of pulmonic stenosis, short stature, easy bruising, and thorax deformities was significantly associated with a PTPN11 mutation, whereas cardiomyopathy was more common in patients without a mutation. On average, PTPN11 mutation-negative probands fulfilled fewer clinical criteria of NS, but more than half-among them all with cardiomyopathy-had the full clinical picture of NS indistinguishable from typical cases with PTPN11 mutation.

    Conclusions: The phenotype of NS due to PTPN11 mutations is clinically unambiguous in the majority of patients and represents a highly penetrant trait. Individuals with the clinical diagnosis of NS but without a PTPN11 mutation presumably represent a heterogeneous group in which patients with cardiomyopathy appear to constitute an interesting subgroup for future research.

    The Journal of pediatrics 2004;144;3;368-74

  • Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation.

    Fragale A, Tartaglia M, Wu J and Gelb BD

    Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA.

    Noonan syndrome is a developmental disorder with dysmorphic facies, short stature, cardiac defects, and skeletal anomalies, which can be caused by missense PTPN11 mutations. PTPN11 encodes Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2 or SHP-2), a protein tyrosine phosphatase that acts in signal transduction downstream to growth factor, hormone, and cytokine receptors. We compared the functional effects of three Noonan syndrome-causative PTPN11 mutations on SHP2's phosphatase activity, interaction with a binding partner, and signal transduction. All SHP2 mutants had significantly increased basal phosphatase activity compared to wild type, but that activity varied significantly between mutants and was further increased after epidermal growth factor stimulation. Cells expressing SHP2 mutants had prolonged extracellular signal-regulated kinase 2 activation, which was ligand-dependent. Binding of SHP2 mutants to Grb2-associated binder-1 was increased and sustained, and tyrosine phosphorylation of both proteins was prolonged. Coexpression of Grb2-associated binder-1-FF, which lacks SHP2 binding motifs, blocked the epidermal growth factor-mediated increase in SHP2's phosphatase activity and resulted in a dramatic reduction of extracellular signal-regulated kinase 2 activation. Taken together, these results document that Noonan syndrome-associated PTPN11 mutations increase SHP2's basal phosphatase activity, with greater activation when residues directly involved in binding at the interface between the N-terminal Src homology 2 and protein tyrosine phosphatase domains are altered. The SHP2 mutants prolonged signal flux through the RAS/mitogen-activated protein kinase (ERK2/MAPK1) pathway in a ligand-dependent manner that required docking through Grb2-associated binder-1 (GAB1), leading to increased cell proliferation.

    Funded by: NCI NIH HHS: CA77467, R01 CA077467; NHLBI NIH HHS: HL71207; NICHD NIH HHS: HD01294

    Human mutation 2004;23;3;267-77

  • Genetics and variation in phenotype in Noonan syndrome.

    Jongmans M, Otten B, Noordam K and van der Burgt I

    Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands.

    Noonan syndrome is a well-known clinical entity comprising multiple congenital anomalies characterized by typical facial features, short stature and congenital heart defect. Approximately 50% of cases are sporadic. Familial cases are generally autosomal dominant. In 2001 a gene responsible for Noonan syndrome, PTPN11, encoding for the non-receptor protein tyrosine phosphatase SHP-2, was identified. Mutation analysis of the PTPN11 gene was carried out in Nijmegen in 150 patients with Noonan syndrome. Mutations were found in 68 patients (45%), the most common being A922G in exon 8. In exon 4 a mutation was found that encoded the C-SH2 domain of the PTPN11 gene in two unique patients who shared some uncommon features. A 218C-->T mutation was found in exon 3 in one patient with Noonan syndrome and mild juvenile myelomonocytic leukaemia.

    Hormone research 2004;62 Suppl 3;56-9

  • Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.

    Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hählen K, Hasle H, Licht JD and Gelb BD

    Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA.

    We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.

    Nature genetics 2003;34;2;148-50

  • PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning.

    Schollen E, Matthijs G, Gewillig M, Fryns JP and Legius E

    Department of Human Genetics, University Hospitals Leuven, Belgium.

    Noonan syndrome (NS, MIM 163950) is an autosomal dominant condition characterised by facial dysmorphy, congenital cardiac defects and short stature. Recently missense mutations in PTPN11, the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2 on 12q24, were identified in 50% of analysed Noonan cases. A large four-generation Belgian family with NS and some features suggestive of cardio-facio-cutaneous syndrome (CFC) was previously used to fine map the Noonan syndrome candidate region to a 5 cM region in 12q24. We now report the identification of a mutation (Gln79Arg) in the PTPN11 gene in this large family. In D. melanogaster and C. elegans the PTPN11 gene has been implicated in oogenesis. In this family two affected females had dizygous twins. This suggests that PTPN11 might also be involved in oogenesis and twinning in humans.

    European journal of human genetics : EJHG 2003;11;1;85-8

  • PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.

    Maheshwari M, Belmont J, Fernbach S, Ho T, Molinari L, Yakub I, Yu F, Combes A, Towbin J, Craigen WJ and Gibbs R

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    We surveyed 16 subjects with the clinical diagnosis of Noonan Syndrome (NS1) from 12 families and their relevant family members for mutations in PTPN11/SHP2 using direct DNA sequencing. We found three different mutations among five families. Two unrelated subjects shared the same de novo missense substitution in exon 13 (S502T); an additional two unrelated families had a mutation in exon 3 (Y63C); and one subject had the amino acid substitution Y62D, also in exon 3. None of the three mutations were present in ethnically matched controls. In the mature protein model, the exon 3 mutants and the exon 13 mutant amino acids cluster at the interface between the N' SH2 domain and the phosphatase catalytic domain. Six of eight subjects with PTPN11/SHP2 mutations had pulmonary valve stenosis while no mutations were identified in those subjects (N = 4) with hypertrophic cardiomyopathy. An additional four subjects with possible Noonan syndrome were evaluated, but no mutations in PTPN11/SHP2 were identified. These results confirm that mutations in PTPN11/SHP2 underlie a common form of Noonan syndrome, and that the disease exhibits both allelic and locus heterogeneity. The observation of recurrent mutations supports the hypothesis that a special class of gain-of-function mutations in SHP2 give rise to Noonan syndrome.

    Funded by: NHGRI NIH HHS: 5U5HG002051; NHLBI NIH HHS: P01 HL67155; NICHD NIH HHS: HD39056

    Human mutation 2002;20;4;298-304

  • PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.

    Kosaki K, Suzuki T, Muroya K, Hasegawa T, Sato S, Matsuo N, Kosaki R, Nagai T, Hasegawa Y and Ogata T

    Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan.

    Noonan syndrome is an autosomal dominant disorder defined by short stature, delayed puberty, and characteristic dysmorphic features. Tartaglia et al. (Nature Genetics, 29:465-468) have recently shown that gain-of-function mutations in the gene PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) cause Noonan syndrome in roughly half of patients that they examined. To further explore the relevance of PTPN11 mutations to the pathogenesis of Noonan syndrome, we analyzed the PTPN11 gene in 21 Japanese patients. Mutation analysis of the 15 coding exons and their flanking introns by denaturing HPLC and direct sequencing revealed six different heterozygous missense mutations (Asp61Gly, Tyr63Cys, Ala72Ser, Thr73Ile, Phe285Ser, and Asn308Asp) in seven cases (six sporadic and one familial). The mutations clustered either in the N-Src homology 2 domain or in the protein-tyrosine phosphatase domain. The clinical features of the mutation-positive and mutation-negative patients were comparable. The results provide further support to the notion that PTPN11 mutations are responsible for the development of Noonan syndrome in a substantial fraction of patients and that relatively infrequent features of Noonan syndrome, such as sensory deafness and bleeding diathesis, can also result from mutations of PTPN11.

    The Journal of clinical endocrinology and metabolism 2002;87;8;3529-33

  • PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

    Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA and Gelb BD

    Department of Pediatrics, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.

    Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for approximately 50% of cases of this genetically heterogeneous disorder in a small cohort. All mutations were missense changes and clustered at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains. A gain of function was postulated as a mechanism for the disease. Here, we report the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains, but defects also affected residues in the C-SH2 domain, as well as in the peptide linking the N-SH2 and C-SH2 domains. Genotype-phenotype analysis revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01), whereas hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene.

    Funded by: NICHD NIH HHS: 5K24 HD 001294, 5P30 HD 28822, K24 HD001294

    American journal of human genetics 2002;70;6;1555-63

  • Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

    Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS and Gelb BD

    Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, USA. tartam02@doc.mssm.edu

    Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.

    Nature genetics 2001;29;4;465-8

  • Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome.

    Tassabehji M, Strachan T, Sharland M, Colley A, Donnai D, Harris R and Thakker N

    University Department of Medical Genetics, St. Mary's Hospital, Manchester, United Kingdom.

    Type 1 neurofibromatosis (NF1), Watson syndrome (WS), and Noonan syndrome (NS) show some overlap in clinical manifestations. In addition, WS has been shown to be linked to markers flanking the NF1 locus and a deletion at the NF1 locus demonstrated in a WS patient. This suggests either that WS and NF1 are allelic or that phenotypes arise from mutations in very closely linked genes. Here we provide evidence for the former by demonstrating a mutation in the NF1 gene in a family with features of both WS and NS. The mutation is an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene. Unlike the mutations previously described in classical NF1, which show a preponderance of null alleles, the mutation in this family would be expected to result in a mutant neurofibromin product.

    Funded by: Wellcome Trust

    American journal of human genetics 1993;53;1;90-5

Literature (26)

Pubmed - human_disease

  • Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome.

    Hung CS, Lin JL, Lee YJ, Lin SP, Chao MC and Lo FS

    Division of Pediatric Endocrinology, Chang Gung Children's Hospital, Taoyuan, Taiwan.

    Noonan syndrome (NS) is an autosomal dominant disorder presenting with characteristic facies, short stature, skeletal anomalies, and congenital heart defects. Mutations in protein-tyrosine phosphatase, nonreceptor-type 11 (PTPN11), encoding SHP-2, account for 33-50% of NS. This study screened for mutations in the PTPN11 gene in 34 Taiwanese patients with NS. Mutation analysis of the 15 coding exons and exon/intron boundaries was performed by polymerase chain reaction and direct sequencing of the PTPN11 gene. We identified 10 different missense mutations in 13 (38%) patients, including a novel missense mutation (855T>G, F285L). These mutations were clustered in exon 3 (n = 6) encoding the N-SH2 domain, exon 4 (n = 2) encoding the C-SH2 domain, and in exons 8 (n = 2) and 13 (n = 3) encoding the PTP domain. In conclusion, this study provides further support that PTPN11 mutations are responsible for Noonan syndrome in Taiwanese patients.

    Journal of the Formosan Medical Association = Taiwan yi zhi 2007;106;2;169-72

  • Severe aortic valvar stenosis in familial Noonan syndrome with mutation of the PTPN11 gene.

    Abadir S, Edouard T and Julia S

    Department of Pediatric Cardiology, Hôpital des Enfants, Toulouse, France. abadir@club-internet.fr

    Noonan's syndrome is an autosomal dominant genetic disease, in which mutation of the PTPN11 gene is found in from one-third to half of all cases. Pulmonary valvar stenosis and myocardiopathy are frequently associated cardiac malformations, whereas aortic valvar stenosis is rarely described. We report, as far as we know, the first case of familial Noonan syndrome with severe aortic valvar stenosis, demonstrating mutation of the PTPN11 gene in the father of the patient.

    Cardiology in the young 2007;17;1;95-7

  • Therapy-related acute myeloid leukemia in a child with Noonan syndrome and clonal duplication of the germline PTPN11 mutation.

    Chantrain CF, Jijon P, De Raedt T, Vermylen C, Poirel HA, Legius E and Brichard B

    Department of Pediatric Hematology-Oncology, St-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium. christophe.chantrain@pedi.ucl.ac.be

    A 4-year-old girl with Noonan syndrome (NS) and constitutive PTPN11 mutation presented with stage 4 neuroblastoma and was treated by intensive chemotherapy. During the treatment, cytogenetic analysis revealed the development of a hyperdiploid clone with duplication of the germline PTPN11 mutation in a morphologically normal bone marrow. A few months later, the patient developed acute myelomonoblastic leukemia with an additional clonal deletion of 7q. Although, we cannot conclude whether there is an association between NS and neuroblastoma, this case suggests that duplication of germline PTPN11 mutations, potentially induced by chemotherapy, contributes to leukemogenesis in patients with NS.

    Pediatric blood & cancer 2007;48;1;101-4

  • Does the rare A172G mutation of PTPN11 gene convey a mild Noonan syndrome phenotype?

    Kitsiou-Tzeli S, Papadopoulou A, Kanaka-Gantenbein C, Fretzayas A, Daskalopoulos D, Kanavakis E and Nicolaidou P

    Department of Medical Genetics, University of Athens, Aghia Sophia Children's Hospital, Thivon & Levadias, Goudi, Athens, Greece. skitsiou@uoa.med.gr

    Background: Noonan syndrome NS (OMIM 163950) is an autosomal dominant developmental disorder characterized mainly by typical facial dysmorphism, growth retardation and variable congenital heart defects. In unrelated individuals with sporadic or familial NS, heterozygous missense point mutations in the gene PTPN11 (OMIM 176876) have been confirmed, with a clustering of mutations in exons 3 and 8, the mutation A922G Asn308Asp accounting for nearly 25% of cases.

    We report a 7-year-old boy with short stature and some other clinical features of NS, who has been investigated by molecular analysis for the presence of mutations in the PTPN11 gene.

    Result: The de novo mutation A172G in the exon 3 of the PTPN11 gene, predicting an Asn58Asp substitution, has been found. To the best of our knowledge, this specific mutation has only been described once before, but this is the first report of detailed clinical data suggesting a mild phenotype.

    Conclusion: Detailed clinical phenotype in every patient with major or minor features of NS and molecular identification of PTPN11 gene mutation may contribute to a better phenotype-genotype correlation.

    Hormone research 2006;66;3;124-31

  • A novel mutation in the PTPN11 gene in a patient with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy.

    Takahashi K, Kogaki S, Kurotobi S, Nasuno S, Ohta M, Okabe H, Wada K, Sakai N, Taniike M and Ozono K

    Department of Developmental Medicine (Paediatrics), Osaka University Graduate School of Medicine, 2-2 Yamada-oka, 565-0871 Suita, Osaka, Japan.

    Unlabelled: A male infant with clinical features of Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy is reported. He manifested severe heart failure and failure to thrive. Administration of propranolol and cibenzoline improved ventricular outflow tract obstruction, leading to catch-up growth. Genetic analysis of the patient revealed a novel missense mutation in the PTPN11 gene.

    Conclusion: This is the first description of a patient with a Gln510Glu mutation in the protein-tyrosine phosphatase, non-receptor type 11 gene. This specific mutation may be associated with a rapidly progressive hypertrophic cardiomyopathy.

    European journal of pediatrics 2005;164;8;497-500

  • Acute myeloid leukemia in an adult Noonan syndrome patient with PTPN11 mutation.

    Matsubara K, Yabe H, Ogata T, Yoshida R and Fukaya T

    American journal of hematology 2005;79;2;171-2

  • A new PTPN11 mutation in juvenile myelomonocytic leukaemia associated with Noonan syndrome.

    Giovannini L, Cavé H, Ferrero-Vacher C, Boutte P and Sirvent N

    Acta paediatrica (Oslo, Norway : 1992) 2005;94;5;636-7

  • [Noonan syndrome and Leopard syndrome linked to mutation of the gene PTPN11].

    Dereure O

    Service de Dermatologie, Hôpital Saint-Eloi, 80, avenue Augustin Fliche, 34295 Montpellier Cedex 5.

    Annales de dermatologie et de venereologie 2005;132;4;400

  • A 3-bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia.

    Yoshida R, Miyata M, Nagai T, Yamazaki T and Ogata T

    Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya, Tokyo 154-8567, Japan.

    A de novo 3-bp deletion (179-181delGTG) was identified at exon 3 of the PTPN11 gene in a female infant with severe Noonan phenotype including hydrops fetalis and juvenile myelomonocytic leukemia. Since the 3-bp deletion is predicted to result in loss of the 60th glycine in the N-SH2 domain that is directly involved in the intramolecular interaction between the N-SH2 and the PTP domains of the PTPN11 protein, this mutation would disrupt the N-SH2/PTP binding in the absence of a phosphopeptide, leading to an excessive phosphatase activity. The results expand the spectrum of PTPN11 mutations in Noonan syndrome (NS), and suggest that a PTPN11 mutation leads to a wide range of clinical features of Noonan syndrome.

    American journal of medical genetics. Part A 2004;128A;1;63-6

  • Genotype-phenotype correlations in Noonan syndrome.

    Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A and Rauch A

    Institute of Human Genetics, Departments of Pediatric Endocrinology and Pediatric Cardiology, University Children's Hospital, Erlangen, Germany.

    Objective: To study genotype-phenotype correlations in a cohort of clinically well-characterized pediatric patients with Noonan syndrome (NS). Study design Fifty-seven unrelated patients with the clinical diagnosis of NS ascertained according to standardized inclusion criteria were prospectively enrolled. Mutational analysis was performed by direct sequencing of the entire coding sequence of the PTPN11 gene.

    Results: Sixteen known and 3 novel PTPN11 mutations could be detected in 60% of index patients, in all familial and in 52% of the sporadic cases. Presence of pulmonic stenosis, short stature, easy bruising, and thorax deformities was significantly associated with a PTPN11 mutation, whereas cardiomyopathy was more common in patients without a mutation. On average, PTPN11 mutation-negative probands fulfilled fewer clinical criteria of NS, but more than half-among them all with cardiomyopathy-had the full clinical picture of NS indistinguishable from typical cases with PTPN11 mutation.

    Conclusions: The phenotype of NS due to PTPN11 mutations is clinically unambiguous in the majority of patients and represents a highly penetrant trait. Individuals with the clinical diagnosis of NS but without a PTPN11 mutation presumably represent a heterogeneous group in which patients with cardiomyopathy appear to constitute an interesting subgroup for future research.

    The Journal of pediatrics 2004;144;3;368-74

  • Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation.

    Fragale A, Tartaglia M, Wu J and Gelb BD

    Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA.

    Noonan syndrome is a developmental disorder with dysmorphic facies, short stature, cardiac defects, and skeletal anomalies, which can be caused by missense PTPN11 mutations. PTPN11 encodes Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2 or SHP-2), a protein tyrosine phosphatase that acts in signal transduction downstream to growth factor, hormone, and cytokine receptors. We compared the functional effects of three Noonan syndrome-causative PTPN11 mutations on SHP2's phosphatase activity, interaction with a binding partner, and signal transduction. All SHP2 mutants had significantly increased basal phosphatase activity compared to wild type, but that activity varied significantly between mutants and was further increased after epidermal growth factor stimulation. Cells expressing SHP2 mutants had prolonged extracellular signal-regulated kinase 2 activation, which was ligand-dependent. Binding of SHP2 mutants to Grb2-associated binder-1 was increased and sustained, and tyrosine phosphorylation of both proteins was prolonged. Coexpression of Grb2-associated binder-1-FF, which lacks SHP2 binding motifs, blocked the epidermal growth factor-mediated increase in SHP2's phosphatase activity and resulted in a dramatic reduction of extracellular signal-regulated kinase 2 activation. Taken together, these results document that Noonan syndrome-associated PTPN11 mutations increase SHP2's basal phosphatase activity, with greater activation when residues directly involved in binding at the interface between the N-terminal Src homology 2 and protein tyrosine phosphatase domains are altered. The SHP2 mutants prolonged signal flux through the RAS/mitogen-activated protein kinase (ERK2/MAPK1) pathway in a ligand-dependent manner that required docking through Grb2-associated binder-1 (GAB1), leading to increased cell proliferation.

    Funded by: NCI NIH HHS: CA77467, R01 CA077467; NHLBI NIH HHS: HL71207; NICHD NIH HHS: HD01294

    Human mutation 2004;23;3;267-77

Pubmed - other

  • Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.

    Zampino G, Pantaleoni F, Carta C, Cobellis G, Vasta I, Neri C, Pogna EA, De Feo E, Delogu A, Sarkozy A, Atzeri F, Selicorni A, Rauen KA, Cytrynbaum CS, Weksberg R, Dallapiccola B, Ballabio A, Gelb BD, Neri G and Tartaglia M

    Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.

    Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.

    Funded by: NHLBI NIH HHS: HL71207; NICHD NIH HHS: HD01294, HD048502; Telethon: GGP04172

    Human mutation 2007;28;3;265-72

  • Mild variable Noonan syndrome in a family with a novel PTPN11 mutation.

    Zenker M, Voss E and Reis A

    Institute of Human Genetics, University of Erlangen--Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany. mzenker@humgenet.uni-erlangen.de

    Noonan syndrome (OMIM 163950) is a common genetic condition with variable clinical expression and genetic heterogeneity. About half of the cases can be accounted to activating mutations in the PTPN11 gene encoding SHP-2. We report on a family with mild, variable expression of Noonan syndrome in five individuals. Clinical manifestations included short stature, craniofacial anomalies and thorax deformity, but none of the affected family members had a heart defect. Sequencing of the entire coding region of PTPN11 revealed a novel mutation c.1226G-->C in exon 11 predicting the amino acid exchange G409A. This mutation is not located in the previously known mutation clusters. Our observation and the recent report of a mutation affecting a neighbouring residue (T411M) in a family with a variable phenotype suggest that mutations in this particular region of SHP-2 may have effects on the protein that differ from those of the classical mutations.

    European journal of medical genetics 2007;50;1;43-7

  • A PTPN11 gene mutation (Y63C) causing Noonan syndrome is not associated with short stature in general population.

    Takahashi I, Utsunomiya M, Inoue K, Takahashi T, Nozaki J, Wada Y, Takada G and Koizumi A

    Department of Pediatrics, Akita University School of Medicine, Japan. tomy@med.akita-u.ac.jp

    Human growth is a highly complicated process, but it is obviously influenced by a genetic factor. Recent genome-wide linkage analyses suggested some genetic regions underlying stature variations. However, any specific genes underlying stature variations have not been identified. Noonan syndrome (NS) is an autosomal dominant disorder clinically characterized by short stature, minor facial anomalies, and congenital heart defects. Recently, PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) has been identified as a major responsible gene for NS, causing about half of the affected individuals. We herein report a large family demonstrating NS caused by one of the common PTPN11 mutations, c.188 A > G (Y63C). In this family, the patients were apparently healthy, but heterozygosity of the c.188 A > G (Y63C) mutation was related to growth impairment. This finding suggested that PTPN11 genetic variants contribute to adult height in the general population. However, c.188 A > G (Y63C) was not identified in 96 short individuals from the general population of 2,281 healthy adults. Thus, it is unlikely that PTPN11 is one of the genes underlying stature variations in the general population.

    The Tohoku journal of experimental medicine 2006;208;3;255-9

  • PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype.

    Bertola DR, Pereira AC, Albano LM, De Oliveira PS, Kim CA and Krieger JE

    Clinical Genetics Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil. deborarb@icr.hcnet.usp.br

    Mutations in the PTPN11 gene are known to cause a large fraction of the cases of Noonan syndrome. The objective of this study was to determine the PTPN11 gene mutation rate in a cohort of clinically well-characterized Brazilian patients with Noonan or Noonan-like syndromes and to study the genotype-phenotype correlation. Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 5 with Noonan-like/multiple giant cell lesion syndrome, and 3 with neurofibromatosis/ Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography (DHPLC) followed by sequencing of amplicons with an aberrant elution profile. We detected missense mutations in the PTPN11 gene in 21 probands with Noonan syndrome (42%), in all 3 patients with LEOPARD syndrome, and in 1 case with Noonan-like/multiple giant cell lesion syndrome. One patient with neurofibromatosis-Noonan syndrome had a mutation in both the PTPN11 and NF1 genes. The only anomalies that reached statistical significance when comparing probands with and without mutations were the hematological abnormalities. Our data confirms that Noonan syndrome is a genetically heterogeneous disorder, with mutations in the PTPN11 gene responsible for roughly 50% of the cases. A definitive genotype-phenotype correlation has not been established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, mutation of the PTPN11 gene is the main causal factor in LEOPARD syndrome, and it also plays a role in neurofibromatosis-Noonan syndrome. Noonan- like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous.

    Genetic testing 2006;10;3;186-91

  • The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.

    Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergsträsser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, Stary J, Trebo M, Zecca M, Gelb BD, Tartaglia M and Loh ML

    University of California, Room HSE-302 Box 0519, San Francisco, CA 94143, USA.

    Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n = 107); (2) patients with NS/MPD (n = 19); and (3) patients with NS (n = 243). Glu76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) being most frequent. Eight of 19 patients with NS/MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS/MPD and JMML.

    Funded by: NCI NIH HHS: K24 CA80916, P30 CA82103, R01 CA104282, R01 CA95621; NHLBI NIH HHS: HL074728, HL71207; NICHD NIH HHS: HD01294; Telethon: GGP04172

    Blood 2005;106;6;2183-5

  • Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation.

    Bertola DR, Pereira AC, de Oliveira PS, Kim CA and Krieger JE

    Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, 05403-900 São Paulo, Brazil. drbetola@attglobal.net

    Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30-50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with downslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene-gene or gene-environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first-degree relatives should also be tested for the specific mutation.

    American journal of medical genetics. Part A 2004;130A;4;378-83

  • Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.

    Yoshida R, Hasegawa T, Hasegawa Y, Nagai T, Kinoshita E, Tanaka Y, Kanegane H, Ohyama K, Onishi T, Hanew K, Okuyama T, Horikawa R, Tanaka T and Ogata T

    Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan.

    We report on PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutation analysis and clinical assessment in 45 patients with Noonan syndrome. Sequence analysis was performed for all of the coding exons 1-15 of PTPN11, revealing a novel 3-bp deletion mutation and 10 recurrent missense mutations in 18 patients. Clinical assessment showed that 1) the growth pattern was similar in mutation-positive and mutation-negative patients, with no significant difference in birth length [-0.6 +/- 2.2 sd (n = 10) vs. -0.6 +/- 1.4 sd (n = 21); P = 0.95], childhood height [-2.6 +/- 1.1 sd (n = 14) vs. -2.1 +/- 1.6 sd (n = 23); P = 0.28], or target height [-0.4 +/- 0.9 sd (n = 14) vs. -0.2 +/- 0.7 sd (n = 17); P = 0.52]; 2) pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients (10 of 18 vs. 6 of 27; P = 0.02), as was atrial septal defect (10 of 18 vs. 4 of 27; P = 0.005), whereas hypertrophic cardiomyopathy was present in five mutation-negative patients only; and 3) other features were grossly similar in the prevalence between mutation-positive and mutation-negative patients, but hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, were exclusively present in mutation-positive patients (5 of 18 vs. 0 of 27; P = 0.007). The results suggest that PTPN11 mutations account for approximately 40% of Noonan syndrome patients, as has been reported previously. Furthermore, assessment of clinical features, in conjunction with data reported previously, implies that the type of cardiovascular lesions and the occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients, whereas the remaining findings are similar in the two groups of patients.

    The Journal of clinical endocrinology and metabolism 2004;89;7;3359-64

  • Genetics and variation in phenotype in Noonan syndrome.

    Jongmans M, Otten B, Noordam K and van der Burgt I

    Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands.

    Noonan syndrome is a well-known clinical entity comprising multiple congenital anomalies characterized by typical facial features, short stature and congenital heart defect. Approximately 50% of cases are sporadic. Familial cases are generally autosomal dominant. In 2001 a gene responsible for Noonan syndrome, PTPN11, encoding for the non-receptor protein tyrosine phosphatase SHP-2, was identified. Mutation analysis of the PTPN11 gene was carried out in Nijmegen in 150 patients with Noonan syndrome. Mutations were found in 68 patients (45%), the most common being A922G in exon 8. In exon 4 a mutation was found that encoded the C-SH2 domain of the PTPN11 gene in two unique patients who shared some uncommon features. A 218C-->T mutation was found in exon 3 in one patient with Noonan syndrome and mild juvenile myelomonocytic leukaemia.

    Hormone research 2004;62 Suppl 3;56-9

  • Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.

    Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hählen K, Hasle H, Licht JD and Gelb BD

    Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA.

    We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.

    Nature genetics 2003;34;2;148-50

  • PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning.

    Schollen E, Matthijs G, Gewillig M, Fryns JP and Legius E

    Department of Human Genetics, University Hospitals Leuven, Belgium.

    Noonan syndrome (NS, MIM 163950) is an autosomal dominant condition characterised by facial dysmorphy, congenital cardiac defects and short stature. Recently missense mutations in PTPN11, the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2 on 12q24, were identified in 50% of analysed Noonan cases. A large four-generation Belgian family with NS and some features suggestive of cardio-facio-cutaneous syndrome (CFC) was previously used to fine map the Noonan syndrome candidate region to a 5 cM region in 12q24. We now report the identification of a mutation (Gln79Arg) in the PTPN11 gene in this large family. In D. melanogaster and C. elegans the PTPN11 gene has been implicated in oogenesis. In this family two affected females had dizygous twins. This suggests that PTPN11 might also be involved in oogenesis and twinning in humans.

    European journal of human genetics : EJHG 2003;11;1;85-8

  • PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.

    Maheshwari M, Belmont J, Fernbach S, Ho T, Molinari L, Yakub I, Yu F, Combes A, Towbin J, Craigen WJ and Gibbs R

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    We surveyed 16 subjects with the clinical diagnosis of Noonan Syndrome (NS1) from 12 families and their relevant family members for mutations in PTPN11/SHP2 using direct DNA sequencing. We found three different mutations among five families. Two unrelated subjects shared the same de novo missense substitution in exon 13 (S502T); an additional two unrelated families had a mutation in exon 3 (Y63C); and one subject had the amino acid substitution Y62D, also in exon 3. None of the three mutations were present in ethnically matched controls. In the mature protein model, the exon 3 mutants and the exon 13 mutant amino acids cluster at the interface between the N' SH2 domain and the phosphatase catalytic domain. Six of eight subjects with PTPN11/SHP2 mutations had pulmonary valve stenosis while no mutations were identified in those subjects (N = 4) with hypertrophic cardiomyopathy. An additional four subjects with possible Noonan syndrome were evaluated, but no mutations in PTPN11/SHP2 were identified. These results confirm that mutations in PTPN11/SHP2 underlie a common form of Noonan syndrome, and that the disease exhibits both allelic and locus heterogeneity. The observation of recurrent mutations supports the hypothesis that a special class of gain-of-function mutations in SHP2 give rise to Noonan syndrome.

    Funded by: NHGRI NIH HHS: 5U5HG002051; NHLBI NIH HHS: P01 HL67155; NICHD NIH HHS: HD39056

    Human mutation 2002;20;4;298-304

  • PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.

    Kosaki K, Suzuki T, Muroya K, Hasegawa T, Sato S, Matsuo N, Kosaki R, Nagai T, Hasegawa Y and Ogata T

    Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan.

    Noonan syndrome is an autosomal dominant disorder defined by short stature, delayed puberty, and characteristic dysmorphic features. Tartaglia et al. (Nature Genetics, 29:465-468) have recently shown that gain-of-function mutations in the gene PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) cause Noonan syndrome in roughly half of patients that they examined. To further explore the relevance of PTPN11 mutations to the pathogenesis of Noonan syndrome, we analyzed the PTPN11 gene in 21 Japanese patients. Mutation analysis of the 15 coding exons and their flanking introns by denaturing HPLC and direct sequencing revealed six different heterozygous missense mutations (Asp61Gly, Tyr63Cys, Ala72Ser, Thr73Ile, Phe285Ser, and Asn308Asp) in seven cases (six sporadic and one familial). The mutations clustered either in the N-Src homology 2 domain or in the protein-tyrosine phosphatase domain. The clinical features of the mutation-positive and mutation-negative patients were comparable. The results provide further support to the notion that PTPN11 mutations are responsible for the development of Noonan syndrome in a substantial fraction of patients and that relatively infrequent features of Noonan syndrome, such as sensory deafness and bleeding diathesis, can also result from mutations of PTPN11.

    The Journal of clinical endocrinology and metabolism 2002;87;8;3529-33

  • PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

    Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA and Gelb BD

    Department of Pediatrics, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.

    Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for approximately 50% of cases of this genetically heterogeneous disorder in a small cohort. All mutations were missense changes and clustered at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains. A gain of function was postulated as a mechanism for the disease. Here, we report the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains, but defects also affected residues in the C-SH2 domain, as well as in the peptide linking the N-SH2 and C-SH2 domains. Genotype-phenotype analysis revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01), whereas hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene.

    Funded by: NICHD NIH HHS: 5K24 HD 001294, 5P30 HD 28822, K24 HD001294

    American journal of human genetics 2002;70;6;1555-63

  • Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

    Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS and Gelb BD

    Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, USA. tartam02@doc.mssm.edu

    Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.

    Nature genetics 2001;29;4;465-8

  • Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome.

    Tassabehji M, Strachan T, Sharland M, Colley A, Donnai D, Harris R and Thakker N

    University Department of Medical Genetics, St. Mary's Hospital, Manchester, United Kingdom.

    Type 1 neurofibromatosis (NF1), Watson syndrome (WS), and Noonan syndrome (NS) show some overlap in clinical manifestations. In addition, WS has been shown to be linked to markers flanking the NF1 locus and a deletion at the NF1 locus demonstrated in a WS patient. This suggests either that WS and NF1 are allelic or that phenotypes arise from mutations in very closely linked genes. Here we provide evidence for the former by demonstrating a mutation in the NF1 gene in a family with features of both WS and NS. The mutation is an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene. Unlike the mutations previously described in classical NF1, which show a preponderance of null alleles, the mutation in this family would be expected to result in a mutant neurofibromin product.

    Funded by: Wellcome Trust

    American journal of human genetics 1993;53;1;90-5

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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