G2Cdb::Human Disease report

Disease id
D00000293
Name
Albright hereditary osteodystrophy
Nervous system disease
yes

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001473 GNAS
GNAS complex locus
Y (1505964) Deletion (D) Y
G00001473 GNAS
GNAS complex locus
Y (10487696) Deletion (D) Y
G00001473 GNAS
GNAS complex locus
Y (11412411) Single nucleotide polymorphism (SNP) Y
G00001473 GNAS
GNAS complex locus
Y (11600516) Microinsertion (MI) Y
G00001473 GNAS
GNAS complex locus
Y (11600516) Insertion (I) Y
G00001473 GNAS
GNAS complex locus
Y (11600516) Deletion (D) Y
G00001473 GNAS
GNAS complex locus
Y (11600516) Splice site mutation (SpS) Y
G00001473 GNAS
GNAS complex locus
Y (12407707) Deletion (D) Y
G00001473 GNAS
GNAS complex locus
Y (12621129) Single nucleotide insertion (SNI) Y
G00001473 GNAS
GNAS complex locus
Y (12621129) Deletion (D) Y
G00001473 GNAS
GNAS complex locus
Y (12621129) Single nucleotide polymorphism (SNP) Y
G00001473 GNAS
GNAS complex locus
Y (12621129) Single nucleotide deletion (SND) Y
G00001473 GNAS
GNAS complex locus
Y (12621129) Microinsertion (MI) Y
G00001473 GNAS
GNAS complex locus
Y (12621129) Nonsense (No) Y
G00001473 GNAS
GNAS complex locus
Y (12656668) Single nucleotide polymorphism (SNP) Y
G00001473 GNAS
GNAS complex locus
Y (16116826) Nonsense (No) Y

References

  • Albright's hereditary osteodystrophy (pseudohypoparathyroidism type Ia): clinical case with a novel mutation of GNAS1.

    Garavelli L, Pedori S, Zanacca C, Caselli G, Loiodice A, Mantovani G, Ammenti A, Virdis R and Banchini G

    Department of Pediatrics, S. Maria Nuova Hospital, Reggio Emilia, Italy. garavelli.livia@asmn.re.it

    Albright's hereditary osteodystrophy is characterized by ectopic calcification and ossification, round face, short hands and feet with short terminal phalanges, short metacarpals (especially 4th and 5th) and absence of the 4th knuckle (brachydactyly type E). Here we describe a case that recently came to our attention of a girl suffering from seizures caused by hypocalcaemia, in which the clinical diagnosis of Albright's hereditary osteodystrophy and Pseudohypoparathyroidism (PHP) (Pseudohypoparathyroidism Ia) was confirmed by DNA molecular analysis. This analysis revealed a novel mutation of GNAS 1, resulting in the nonsense mutation of exon 13 (CAG-->TAG, codon 384). This result expands the spectrum of GNAS1 mutations associated with this disorder.

    Acta bio-medica : Atenei Parmensis 2005;76;1;45-8

  • Molecular analysis of the GNAS1 gene for the correct diagnosis of Albright hereditary osteodystrophy and pseudohypoparathyroidism.

    De Sanctis L, Romagnolo D, Olivero M, Buzi F, Maghnie M, Scirè G, Crino A, Baroncelli GI, Salerno M, Di Maio S, Cappa M, Grosso S, Rigon F, Lala R, De Sanctis C and Dianzani I

    Department of Pediatric Sciences, 94, Piazza Polonia, 10126 Torino, Italy; ldesanct@pediatria.unito.it

    Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH resistance and classified as types Ia, Ib, Ic, and II, according to its different pathogenesis and phenotype. PHP-Ia patients show Gsalpha protein deficiency, PTH resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous mutations in the GNAS1 gene encoding the Gsalpha protein have been identified both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP in the same family when inherited from the maternal and the paternal allele, respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether molecular diagnosis is a useful tool to characterize AHO and PHP when testing for Gsalpha activity and PTH resistance is not available, we have performed GNAS1 mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP patients, eight of which have not been reported previously. Inheritance was ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were inherited from the mothers, who had AHO (PPHP), consistent with the proposed imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia and PPHP in the mutated patients. Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia.

    Pediatric research 2003;53;5;749-55

  • A new heterozygous mutation (L338N) in the human Gsalpha (GNAS1) gene as a cause for congenital hypothyroidism in Albright's hereditary osteodystrophy.

    Pohlenz J, Ahrens W and Hiort O

    Children's Hospital, Johannes Gutenberg-University, Langenbeckstrasse 1, D-55101 Mainz, Germany. pohlenz@mail.uni-mainz.de

    Objective: To identify the molecular defect by which psychomotor retardation is caused in two brothers with congenital hypothyroidism who received adequate treatment with l-thyroxine.

    A six-year-old boy presented with psychomotor retardation and congenital primary hypothyroidism (CH). The patient had a normal blood thyrotrophin (TSH) level on neonatal screening, but low total serum thyroxine and triiodothyronine concentrations prompting thyroid hormone substitution shortly after birth. Nevertheless, psychomotor development was retarded and the patient underwent further investigation. Typical features of Albright's hereditary osteodystrophy (AHO) such as round face, obesity, and shortened 1st, 4th and 5th metacarpals were found.

    Further investigation confirmed AHO with pseudohypoparathyroidism (PHP) type Ia. The boy had a mild resistance to parathyroid hormone and a reduced adenylyl cyclase stimulating protein (Gsalpha) activity in erythrocytes. DNA analysis detected a new heterozygous mutation (L338N) in the Gsalpha protein (GNAS1) gene. This mutation was also present in the patient's brother who had similar features and was also treated with thyroid hormone because of CH, and in the phenotypically normal-looking mother who had a normal calcium metabolism but a reduced Gsalpha protein activity in erythrocytes suggestive of pseudopseudohypoparathyroidism.

    Conclusion: In patients with CH, in whom the neurological outcome is poor even under adequate thyroid hormone substitution, PHP Ia may be suspected, especially when symptoms of AHO are present.

    European journal of endocrinology 2003;148;4;463-8

  • Constitutional deletion of chromosome 20q in two patients affected with albright hereditary osteodystrophy.

    Aldred MA, Aftimos S, Hall C, Waters KS, Thakker RV, Trembath RC and Brueton L

    Division of Medical Genetics, University of Leicester, and Department of Molecular Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK. maldred@hgmp.mrc.ac.uk

    Albright hereditary osteodystrophy (AHO) results from heterozygous inactivation of G(s)alpha, encoded by the GNAS1 locus on the distal long arm of chromosome 20. This autosomal dominant condition is characterized by short stature, obesity, shortening of the metacarpals and metatarsals, and variable mental retardation and may also include end-organ resistance to multiple hormones. Small insertions and deletions or point mutations of GNAS1 are found in approximately 80% of patients with AHO. The remainder may be accounted for by larger genomic rearrangements, but none have been reported to date. We now describe two patients with constitutional 20q deletions and features of AHO. Such deletions are rare in the published literature and have not previously been associated with AHO. Molecular genetic analysis confirmed complete deletion of GNAS1 in both patients. Parental origin could be determined in both cases and provides further support for the parent-of-origin effect on the biochemical status of patients with AHO.

    American journal of medical genetics 2002;113;2;167-72

  • Analysis of the GNAS1 gene in Albright's hereditary osteodystrophy.

    Ahrens W, Hiort O, Staedt P, Kirschner T, Marschke C and Kruse K

    Department of Pediatrics, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. ahrens@paedia.ukl.mu-luebeck.de

    Albright's hereditary osteodystrophy (AHO) is characterized by phenotypic signs that typically include brachydactyly and sc calcifications occurring with or without hormone resistance toward PTH or other hormones such as thyroid hormone or gonadotropins. Different inactivating mutations of the gene GNAS1 encoding Gsalpha lead to a reduced Gsalpha protein activity in patients with AHO and pseudohypoparathyroidism type Ia or without resistance to PTH (pseudopseudohypoparathyroidism). We investigated 29 unrelated patients with AHO and pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism and their affected family members performing functional and molecular genetic analysis of Gsalpha. In vitro determination of Gsalpha protein activity in erythrocyte membranes was followed by the investigation of the whole coding region of the GNAS1 gene using PCR, nonisotopic single strand conformation analysis, and direct sequencing of the PCR products. All patients showed a reduced Gsalpha protein activity (mean 59% compared with healthy controls). In 21/29 (72%) patients, 15 different mutations in GNAS1 including 11 novel mutations were detected. In addition we add five unrelated patients with a previously described 4 bp deletion in exon 7 (Delta GACT, codon 189/190), confirming the presence of a hot spot for loss of function mutations in GNAS1. In eight patients, no molecular abnormality was found in the GNAS1 gene despite a functional defect of Gsalpha. We conclude that biochemical and molecular analysis of Gsalpha and its gene GNAS1 can be valuable tools to confirm the diagnosis of AHO. However, in some patients with reduced activity of Gsalpha, the molecular defect cannot be detected in the exons encoding the common form of Gsalpha.

    The Journal of clinical endocrinology and metabolism 2001;86;10;4630-4

  • [Albright hereditary osteodystrophy: identification of a novel mutation in a family].

    Bastida Eizaguirre M, Iturbe Ortiz De Urbina R, Arto Urzainqui M, Ezquerra Larreina R and Escalada San Martín J

    Servicios de Pediatría Endocrinología. Hospital Santiago Apóstol. Vitoria. mbastida@hsan.osakidetza.net

    Studies to detect mutations in the GNAS1 gene were performed in a male patient with features of Albright hereditary osteodystrophy and resistance of target tissues to parathyroid hormone (Pseudohypoparathyroidism Ia). The same investigations were carried out in the patient's mother who showed somatic features of Albright's hereditary osteodystrophy and brachymetacarpia without resistance to parathyroid hormone (Pseudopseudohypoparathyroidism). A point mutation designated c.794GA (R265H) in exon 10 of GNAS1 was identified in DNA from the patient and his mother. This novel mutation in exon 10 of GNA

    Anales espanoles de pediatria 2001;54;6;598-600

  • Identification of two novel deletion mutations within the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy.

    Yu D, Yu S, Schuster V, Kruse K, Clericuzio CL and Weinstein LS

    Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

    Albright hereditary osteodystrophy (AHO) is a genetic disorder characterized by short stature, skeletal defects, and obesity. Within AHO kindreds, some affected family members have only the somatic features of AHO [pseudopseudohypoparathyroidism (PPHP)], whereas others have these features in association with resistance to multiple hormones that stimulate adenylyl cyclase within their target tissues [pseudohypoparathyroidism type Ia (PHP Ia)]. Affected members of most AHO kindreds (both those with PPHP and those with PHP Ia) have a partial deficiency of Gs alpha, the alpha-subunit of the G protein that couples receptors to adenylyl cyclase stimulation, and in a number of cases heterozygous loss of function mutations within the Gs alpha gene (GNAS1) have been identified. Using PCR with the attachment of a high melting domain (GC-clamp) and temperature gradient gel electrophoresis, two novel heterozygous frameshift mutations within GNAS1 were found in two AHO kindreds. In one kindred all affected members (both PHP Ia and PPHP) had a heterozygous 2-bp deletion in exon 8, whereas in the second kindred a heterozygous 2-bp deletion in exon 4 was identified in all affected members examined. In both cases the frameshift encoded a premature termination codon several codons downstream of the deletion. In the latter kindred affected members were previously shown to have decreased levels of GNAS1 messenger ribonucleic acid expression. These results further underscore the genetic heterogeneity of AHO and provides further evidence that PHP Ia and PPHP are two clinical presentations of a common genetic defect. Serial measurements of thyroid function in members of kindred 1 indicate that TSH resistance progresses with age and becomes more evident after the first year of life.

    The Journal of clinical endocrinology and metabolism 1999;84;9;3254-9

  • A heterozygous 4-bp deletion mutation in the Gs alpha gene (GNAS1) in a patient with Albright hereditary osteodystrophy.

    Weinstein LS, Gejman PV, de Mazancourt P, American N and Spiegel AM

    Molecular Pathophysiology Branch, National Institute of Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.

    Several heterozygous mutations within the gene encoding the alpha-subunit of Gs (GNAS1), the G protein that stimulates adenylyl cyclase, have been previously identified in patients with Albright hereditary osteodystrophy (AHO). We have now identified a fourth GNAS1 mutation from an AHO patient. Amplification by the polymerase chain reaction (PCR) of a genomic fragment encompassing GNAS1 exons 7 and 8 from one patient resulted in a product with aberrant migration on nondenaturing polyacrylamide and agarose gels. Direct DNA sequencing identified a 4-bp deletion in one allele of exon 7 encoding a frameshift with a premature stop codon. Analysis of lymphocyte RNA by reverse transcription-PCR and direct sequencing showed that the GNAS1 allele bearing the mutation is not expressed as mRNA. Consistent with this, Northern analysis revealed an approximate 50% deficiency in steady-state levels of GNAS1 mRNA. These findings further illustrate the heterogeneity of GNAS1 gene defects in AHO.

    Genomics 1992;13;4;1319-21

Literature (8)

Pubmed - human_disease

  • Albright's hereditary osteodystrophy (pseudohypoparathyroidism type Ia): clinical case with a novel mutation of GNAS1.

    Garavelli L, Pedori S, Zanacca C, Caselli G, Loiodice A, Mantovani G, Ammenti A, Virdis R and Banchini G

    Department of Pediatrics, S. Maria Nuova Hospital, Reggio Emilia, Italy. garavelli.livia@asmn.re.it

    Albright's hereditary osteodystrophy is characterized by ectopic calcification and ossification, round face, short hands and feet with short terminal phalanges, short metacarpals (especially 4th and 5th) and absence of the 4th knuckle (brachydactyly type E). Here we describe a case that recently came to our attention of a girl suffering from seizures caused by hypocalcaemia, in which the clinical diagnosis of Albright's hereditary osteodystrophy and Pseudohypoparathyroidism (PHP) (Pseudohypoparathyroidism Ia) was confirmed by DNA molecular analysis. This analysis revealed a novel mutation of GNAS 1, resulting in the nonsense mutation of exon 13 (CAG-->TAG, codon 384). This result expands the spectrum of GNAS1 mutations associated with this disorder.

    Acta bio-medica : Atenei Parmensis 2005;76;1;45-8

  • Constitutional deletion of chromosome 20q in two patients affected with albright hereditary osteodystrophy.

    Aldred MA, Aftimos S, Hall C, Waters KS, Thakker RV, Trembath RC and Brueton L

    Division of Medical Genetics, University of Leicester, and Department of Molecular Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK. maldred@hgmp.mrc.ac.uk

    Albright hereditary osteodystrophy (AHO) results from heterozygous inactivation of G(s)alpha, encoded by the GNAS1 locus on the distal long arm of chromosome 20. This autosomal dominant condition is characterized by short stature, obesity, shortening of the metacarpals and metatarsals, and variable mental retardation and may also include end-organ resistance to multiple hormones. Small insertions and deletions or point mutations of GNAS1 are found in approximately 80% of patients with AHO. The remainder may be accounted for by larger genomic rearrangements, but none have been reported to date. We now describe two patients with constitutional 20q deletions and features of AHO. Such deletions are rare in the published literature and have not previously been associated with AHO. Molecular genetic analysis confirmed complete deletion of GNAS1 in both patients. Parental origin could be determined in both cases and provides further support for the parent-of-origin effect on the biochemical status of patients with AHO.

    American journal of medical genetics 2002;113;2;167-72

  • [Albright hereditary osteodystrophy: identification of a novel mutation in a family].

    Bastida Eizaguirre M, Iturbe Ortiz De Urbina R, Arto Urzainqui M, Ezquerra Larreina R and Escalada San Martín J

    Servicios de Pediatría Endocrinología. Hospital Santiago Apóstol. Vitoria. mbastida@hsan.osakidetza.net

    Studies to detect mutations in the GNAS1 gene were performed in a male patient with features of Albright hereditary osteodystrophy and resistance of target tissues to parathyroid hormone (Pseudohypoparathyroidism Ia). The same investigations were carried out in the patient's mother who showed somatic features of Albright's hereditary osteodystrophy and brachymetacarpia without resistance to parathyroid hormone (Pseudopseudohypoparathyroidism). A point mutation designated c.794GA (R265H) in exon 10 of GNAS1 was identified in DNA from the patient and his mother. This novel mutation in exon 10 of GNA

    Anales espanoles de pediatria 2001;54;6;598-600

Pubmed - other

  • Molecular analysis of the GNAS1 gene for the correct diagnosis of Albright hereditary osteodystrophy and pseudohypoparathyroidism.

    De Sanctis L, Romagnolo D, Olivero M, Buzi F, Maghnie M, Scirè G, Crino A, Baroncelli GI, Salerno M, Di Maio S, Cappa M, Grosso S, Rigon F, Lala R, De Sanctis C and Dianzani I

    Department of Pediatric Sciences, 94, Piazza Polonia, 10126 Torino, Italy; ldesanct@pediatria.unito.it

    Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH resistance and classified as types Ia, Ib, Ic, and II, according to its different pathogenesis and phenotype. PHP-Ia patients show Gsalpha protein deficiency, PTH resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous mutations in the GNAS1 gene encoding the Gsalpha protein have been identified both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP in the same family when inherited from the maternal and the paternal allele, respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether molecular diagnosis is a useful tool to characterize AHO and PHP when testing for Gsalpha activity and PTH resistance is not available, we have performed GNAS1 mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP patients, eight of which have not been reported previously. Inheritance was ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were inherited from the mothers, who had AHO (PPHP), consistent with the proposed imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia and PPHP in the mutated patients. Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia.

    Pediatric research 2003;53;5;749-55

  • A new heterozygous mutation (L338N) in the human Gsalpha (GNAS1) gene as a cause for congenital hypothyroidism in Albright's hereditary osteodystrophy.

    Pohlenz J, Ahrens W and Hiort O

    Children's Hospital, Johannes Gutenberg-University, Langenbeckstrasse 1, D-55101 Mainz, Germany. pohlenz@mail.uni-mainz.de

    Objective: To identify the molecular defect by which psychomotor retardation is caused in two brothers with congenital hypothyroidism who received adequate treatment with l-thyroxine.

    A six-year-old boy presented with psychomotor retardation and congenital primary hypothyroidism (CH). The patient had a normal blood thyrotrophin (TSH) level on neonatal screening, but low total serum thyroxine and triiodothyronine concentrations prompting thyroid hormone substitution shortly after birth. Nevertheless, psychomotor development was retarded and the patient underwent further investigation. Typical features of Albright's hereditary osteodystrophy (AHO) such as round face, obesity, and shortened 1st, 4th and 5th metacarpals were found.

    Further investigation confirmed AHO with pseudohypoparathyroidism (PHP) type Ia. The boy had a mild resistance to parathyroid hormone and a reduced adenylyl cyclase stimulating protein (Gsalpha) activity in erythrocytes. DNA analysis detected a new heterozygous mutation (L338N) in the Gsalpha protein (GNAS1) gene. This mutation was also present in the patient's brother who had similar features and was also treated with thyroid hormone because of CH, and in the phenotypically normal-looking mother who had a normal calcium metabolism but a reduced Gsalpha protein activity in erythrocytes suggestive of pseudopseudohypoparathyroidism.

    Conclusion: In patients with CH, in whom the neurological outcome is poor even under adequate thyroid hormone substitution, PHP Ia may be suspected, especially when symptoms of AHO are present.

    European journal of endocrinology 2003;148;4;463-8

  • Analysis of the GNAS1 gene in Albright's hereditary osteodystrophy.

    Ahrens W, Hiort O, Staedt P, Kirschner T, Marschke C and Kruse K

    Department of Pediatrics, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. ahrens@paedia.ukl.mu-luebeck.de

    Albright's hereditary osteodystrophy (AHO) is characterized by phenotypic signs that typically include brachydactyly and sc calcifications occurring with or without hormone resistance toward PTH or other hormones such as thyroid hormone or gonadotropins. Different inactivating mutations of the gene GNAS1 encoding Gsalpha lead to a reduced Gsalpha protein activity in patients with AHO and pseudohypoparathyroidism type Ia or without resistance to PTH (pseudopseudohypoparathyroidism). We investigated 29 unrelated patients with AHO and pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism and their affected family members performing functional and molecular genetic analysis of Gsalpha. In vitro determination of Gsalpha protein activity in erythrocyte membranes was followed by the investigation of the whole coding region of the GNAS1 gene using PCR, nonisotopic single strand conformation analysis, and direct sequencing of the PCR products. All patients showed a reduced Gsalpha protein activity (mean 59% compared with healthy controls). In 21/29 (72%) patients, 15 different mutations in GNAS1 including 11 novel mutations were detected. In addition we add five unrelated patients with a previously described 4 bp deletion in exon 7 (Delta GACT, codon 189/190), confirming the presence of a hot spot for loss of function mutations in GNAS1. In eight patients, no molecular abnormality was found in the GNAS1 gene despite a functional defect of Gsalpha. We conclude that biochemical and molecular analysis of Gsalpha and its gene GNAS1 can be valuable tools to confirm the diagnosis of AHO. However, in some patients with reduced activity of Gsalpha, the molecular defect cannot be detected in the exons encoding the common form of Gsalpha.

    The Journal of clinical endocrinology and metabolism 2001;86;10;4630-4

  • Identification of two novel deletion mutations within the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy.

    Yu D, Yu S, Schuster V, Kruse K, Clericuzio CL and Weinstein LS

    Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

    Albright hereditary osteodystrophy (AHO) is a genetic disorder characterized by short stature, skeletal defects, and obesity. Within AHO kindreds, some affected family members have only the somatic features of AHO [pseudopseudohypoparathyroidism (PPHP)], whereas others have these features in association with resistance to multiple hormones that stimulate adenylyl cyclase within their target tissues [pseudohypoparathyroidism type Ia (PHP Ia)]. Affected members of most AHO kindreds (both those with PPHP and those with PHP Ia) have a partial deficiency of Gs alpha, the alpha-subunit of the G protein that couples receptors to adenylyl cyclase stimulation, and in a number of cases heterozygous loss of function mutations within the Gs alpha gene (GNAS1) have been identified. Using PCR with the attachment of a high melting domain (GC-clamp) and temperature gradient gel electrophoresis, two novel heterozygous frameshift mutations within GNAS1 were found in two AHO kindreds. In one kindred all affected members (both PHP Ia and PPHP) had a heterozygous 2-bp deletion in exon 8, whereas in the second kindred a heterozygous 2-bp deletion in exon 4 was identified in all affected members examined. In both cases the frameshift encoded a premature termination codon several codons downstream of the deletion. In the latter kindred affected members were previously shown to have decreased levels of GNAS1 messenger ribonucleic acid expression. These results further underscore the genetic heterogeneity of AHO and provides further evidence that PHP Ia and PPHP are two clinical presentations of a common genetic defect. Serial measurements of thyroid function in members of kindred 1 indicate that TSH resistance progresses with age and becomes more evident after the first year of life.

    The Journal of clinical endocrinology and metabolism 1999;84;9;3254-9

  • A heterozygous 4-bp deletion mutation in the Gs alpha gene (GNAS1) in a patient with Albright hereditary osteodystrophy.

    Weinstein LS, Gejman PV, de Mazancourt P, American N and Spiegel AM

    Molecular Pathophysiology Branch, National Institute of Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.

    Several heterozygous mutations within the gene encoding the alpha-subunit of Gs (GNAS1), the G protein that stimulates adenylyl cyclase, have been previously identified in patients with Albright hereditary osteodystrophy (AHO). We have now identified a fourth GNAS1 mutation from an AHO patient. Amplification by the polymerase chain reaction (PCR) of a genomic fragment encompassing GNAS1 exons 7 and 8 from one patient resulted in a product with aberrant migration on nondenaturing polyacrylamide and agarose gels. Direct DNA sequencing identified a 4-bp deletion in one allele of exon 7 encoding a frameshift with a premature stop codon. Analysis of lymphocyte RNA by reverse transcription-PCR and direct sequencing showed that the GNAS1 allele bearing the mutation is not expressed as mRNA. Consistent with this, Northern analysis revealed an approximate 50% deficiency in steady-state levels of GNAS1 mRNA. These findings further illustrate the heterogeneity of GNAS1 gene defects in AHO.

    Genomics 1992;13;4;1319-21

© 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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