G2Cdb::Human Disease report

Disease id
D00000264
Name
Progressive osseous heteroplasia
Nervous system disease
no

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001473 GNAS
GNAS complex locus
Y (11092390) Nonsense (No) Y
G00001473 GNAS
GNAS complex locus
Y (11784876) Unknown (?) Y
G00001473 GNAS
GNAS complex locus
Y (14723729) Microinsertion (MI) Y

References

  • Progressive osseous heteroplasia resulting from a new mutation in the GNAS1 gene.

    Chan I, Hamada T, Hardman C, McGrath JA and Child FJ

    Department of Dermatology, St Mary's Hospital, London, UK. ien.chan@kcl.ac.uk

    Progressive osseous heteroplasia (OMIM 166350) is a rare autosomal dominant condition that presents in childhood as dermal ossification and may progress deeper to involve subcutaneous fat and connective tissue. Recently, paternally inherited inactivating mutations in the GNAS1 gene on chromosome 20q13 have been implicated in the pathogenesis, although sporadic cases have also been reported. We report a 9-year-old British Chinese girl with progressive osseous heteroplasia resulting from a de novo missense mutation (W281R) in the GNAS1 gene. She is of small stature (0.4th centile) and started to develop skin lesions at the age of 9 months. These have been confirmed histologically as osteoma cutis. She is of normal intelligence and development and has no dysmorphic features. The GNAS1 gene exhibits imprinting and maternally inherited mutations have previously been shown to result in Albright's hereditary osteodystrophy (OMIM 103580) with pseudohypothyroidism type 1a, whereas paternally inherited mutations result in progressive osseous heteroplasia or the Albright's hereditary osteodystrophy phenotype with pseudopseudohypothyroidism (OMIM 300800). With only nine mutations of the GNAS1 gene reported so far in progressive osseous heteroplasia, this new mutation helps to extend further the genotype-phenotype correlation.

    Clinical and experimental dermatology 2004;29;1;77-80

  • Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia.

    Shore EM, Ahn J, Jan de Beur S, Li M, Xu M, Gardner RJ, Zasloff MA, Whyte MP, Levine MA and Kaplan FS

    Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia 19104-6018, USA. shore@mail.med.upenn.edu

    Background: Progressive osseous heteroplasia (POH), an autosomal dominant disorder, is characterized by extensive dermal ossification during childhood, followed by disabling and widespread heterotopic ossification of skeletal muscle and deep connective tissue. Occasional reports of mild heterotopic ossification in Albright's hereditary osteodystrophy (AHO) and a recent report of two patients with AHO who had atypically extensive heterotopic ossification suggested a common genetic basis for the two disorders. AHO is caused by heterozygous inactivating mutations in the GNAS1 gene that result in decreased expression or function of the alpha subunit of the stimulatory G protein (Gsalpha) of adenylyl cyclase.

    Methods: We tested the hypothesis that GNAS1 mutations cause POH, using the polymerase chain reaction to amplify GNAS1 exons and exon-intron boundaries in 18 patients with sporadic or familial POH.

    Results: Heterozygous inactivating GNAS1 mutations were identified in 13 of the 18 probands with POH. The defective allele in POH is inherited exclusively from fathers, a result consistent with a model of imprinting for GNAS1. Direct evidence that the same mutation can cause either POH or AHO was observed within a single family, in which the phenotype correlated with the parental origin of the mutant allele.

    Conclusions: Paternally inherited inactivating GNAS1 mutations cause POH. This finding extends the range of phenotypes derived from haplo insufficiency of GNAS1, provides evidence that imprinting is a regulatory mechanism for GNAS1 expression, and suggests that Gsalpha is a critical negative regulator of osteogenic commitment in nonosseous connective tissues.

    Funded by: NIAMS NIH HHS: R01 AR046831, R01-AR41916, R01-AR46831; NIDDK NIH HHS: R01-DK34281

    The New England journal of medicine 2002;346;2;99-106

  • Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification.

    Eddy MC, Jan De Beur SM, Yandow SM, McAlister WH, Shore EM, Kaplan FS, Whyte MP and Levine MA

    Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri 63131, USA.

    Progressive osseous heteroplasia (POH) is a rare disorder characterized by dermal ossification beginning in infancy followed by increasing and extensive bone formation in deep muscle and fascia. We describe two unrelated girls with typical clinical, radiographic, and histological features of POH who also have findings of another uncommon heritable disorder, Albright hereditary osteodystrophy (AHO). One patient has mild brachydactyly but no endocrinopathy, whereas the other manifests brachydactyly, obesity, and target tissue resistance to thyrotropin and parathyroid hormone (PTH). Levels of the alpha-subunit of the G protein (Gsalpha) were reduced in erythrocyte membranes from both girls and a nonsense mutation (Q12X) in exon 1 of the GNAS1 gene was identified in genomic DNA from the mildly affected patient. Features of POH and AHO in two individuals suggest that these conditions share a similar molecular basis and pathogenesis and that isolated severe extraskeletal ossification may be another manifestation of Gsalpha deficiency.

    Funded by: NIAMS NIH HHS: 2R01-AR41916-04, R01 AR046831; NIDDK NIH HHS: DK 34281; PHS HHS: GCRC 00055

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2000;15;11;2074-83

Literature (3)

Pubmed - human_disease

  • Progressive osseous heteroplasia resulting from a new mutation in the GNAS1 gene.

    Chan I, Hamada T, Hardman C, McGrath JA and Child FJ

    Department of Dermatology, St Mary's Hospital, London, UK. ien.chan@kcl.ac.uk

    Progressive osseous heteroplasia (OMIM 166350) is a rare autosomal dominant condition that presents in childhood as dermal ossification and may progress deeper to involve subcutaneous fat and connective tissue. Recently, paternally inherited inactivating mutations in the GNAS1 gene on chromosome 20q13 have been implicated in the pathogenesis, although sporadic cases have also been reported. We report a 9-year-old British Chinese girl with progressive osseous heteroplasia resulting from a de novo missense mutation (W281R) in the GNAS1 gene. She is of small stature (0.4th centile) and started to develop skin lesions at the age of 9 months. These have been confirmed histologically as osteoma cutis. She is of normal intelligence and development and has no dysmorphic features. The GNAS1 gene exhibits imprinting and maternally inherited mutations have previously been shown to result in Albright's hereditary osteodystrophy (OMIM 103580) with pseudohypothyroidism type 1a, whereas paternally inherited mutations result in progressive osseous heteroplasia or the Albright's hereditary osteodystrophy phenotype with pseudopseudohypothyroidism (OMIM 300800). With only nine mutations of the GNAS1 gene reported so far in progressive osseous heteroplasia, this new mutation helps to extend further the genotype-phenotype correlation.

    Clinical and experimental dermatology 2004;29;1;77-80

  • Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification.

    Eddy MC, Jan De Beur SM, Yandow SM, McAlister WH, Shore EM, Kaplan FS, Whyte MP and Levine MA

    Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri 63131, USA.

    Progressive osseous heteroplasia (POH) is a rare disorder characterized by dermal ossification beginning in infancy followed by increasing and extensive bone formation in deep muscle and fascia. We describe two unrelated girls with typical clinical, radiographic, and histological features of POH who also have findings of another uncommon heritable disorder, Albright hereditary osteodystrophy (AHO). One patient has mild brachydactyly but no endocrinopathy, whereas the other manifests brachydactyly, obesity, and target tissue resistance to thyrotropin and parathyroid hormone (PTH). Levels of the alpha-subunit of the G protein (Gsalpha) were reduced in erythrocyte membranes from both girls and a nonsense mutation (Q12X) in exon 1 of the GNAS1 gene was identified in genomic DNA from the mildly affected patient. Features of POH and AHO in two individuals suggest that these conditions share a similar molecular basis and pathogenesis and that isolated severe extraskeletal ossification may be another manifestation of Gsalpha deficiency.

    Funded by: NIAMS NIH HHS: 2R01-AR41916-04, R01 AR046831; NIDDK NIH HHS: DK 34281; PHS HHS: GCRC 00055

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2000;15;11;2074-83

Pubmed - other

  • Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia.

    Shore EM, Ahn J, Jan de Beur S, Li M, Xu M, Gardner RJ, Zasloff MA, Whyte MP, Levine MA and Kaplan FS

    Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia 19104-6018, USA. shore@mail.med.upenn.edu

    Background: Progressive osseous heteroplasia (POH), an autosomal dominant disorder, is characterized by extensive dermal ossification during childhood, followed by disabling and widespread heterotopic ossification of skeletal muscle and deep connective tissue. Occasional reports of mild heterotopic ossification in Albright's hereditary osteodystrophy (AHO) and a recent report of two patients with AHO who had atypically extensive heterotopic ossification suggested a common genetic basis for the two disorders. AHO is caused by heterozygous inactivating mutations in the GNAS1 gene that result in decreased expression or function of the alpha subunit of the stimulatory G protein (Gsalpha) of adenylyl cyclase.

    Methods: We tested the hypothesis that GNAS1 mutations cause POH, using the polymerase chain reaction to amplify GNAS1 exons and exon-intron boundaries in 18 patients with sporadic or familial POH.

    Results: Heterozygous inactivating GNAS1 mutations were identified in 13 of the 18 probands with POH. The defective allele in POH is inherited exclusively from fathers, a result consistent with a model of imprinting for GNAS1. Direct evidence that the same mutation can cause either POH or AHO was observed within a single family, in which the phenotype correlated with the parental origin of the mutant allele.

    Conclusions: Paternally inherited inactivating GNAS1 mutations cause POH. This finding extends the range of phenotypes derived from haplo insufficiency of GNAS1, provides evidence that imprinting is a regulatory mechanism for GNAS1 expression, and suggests that Gsalpha is a critical negative regulator of osteogenic commitment in nonosseous connective tissues.

    Funded by: NIAMS NIH HHS: R01 AR046831, R01-AR41916, R01-AR46831; NIDDK NIH HHS: R01-DK34281

    The New England journal of medicine 2002;346;2;99-106

© 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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