G2Cdb::Allele report

Mutation type
?

Altered genes (1)

Gene Symbol Species Description
G00001473 GNAS Homo sapiens GNAS complex locus

Diseases (1)

Disease Description Nervous effect
D00000264 Progressive osseous heteroplasia N

Literature (1)

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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