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

Eileen M. Shore, Jaimo Ahn, Suzanne M Jan De Beur, Ming Li, Meiqi Xu, R. J. McKinlay Gardner, Michael A. Zasloff, Michael P. Whyte, Michael A. Levine, Frederick S. Kaplan

Research output: Contribution to journalArticle

Abstract

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 (G sα) 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 haploinsufficiency of GNAS1, provides evidence that imprinting is a regulatory mechanism for GNAS1 expression, and suggests that G sα is a critical negative regulator of osteogenic commitment in nonosseous connective tissues.

Original languageEnglish (US)
Pages (from-to)99-106
Number of pages8
JournalNew England Journal of Medicine
Volume346
Issue number2
DOIs
StatePublished - Jan 10 2002

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Mutation
Heterotopic Ossification
Genes
Connective Tissue
Exons
Alleles
GTP-Binding Protein alpha Subunits
Phenotype
Haploinsufficiency
Progressive Osseous Heteroplasia
Paternal Inheritance
Adenylyl Cyclases
Osteogenesis
Fathers
Introns
Skeletal Muscle
Polymerase Chain Reaction
Skin
Albright's hereditary osteodystrophy
Imprinting (Psychology)

ASJC Scopus subject areas

  • Medicine(all)

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Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. / Shore, Eileen M.; Ahn, Jaimo; Jan De Beur, Suzanne M; Li, Ming; Xu, Meiqi; McKinlay Gardner, R. J.; Zasloff, Michael A.; Whyte, Michael P.; Levine, Michael A.; Kaplan, Frederick S.

In: New England Journal of Medicine, Vol. 346, No. 2, 10.01.2002, p. 99-106.

Research output: Contribution to journalArticle

Shore, EM, Ahn, J, Jan De Beur, SM, Li, M, Xu, M, McKinlay Gardner, RJ, Zasloff, MA, Whyte, MP, Levine, MA & Kaplan, FS 2002, 'Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia', New England Journal of Medicine, vol. 346, no. 2, pp. 99-106. https://doi.org/10.1056/NEJMoa011262
Shore, Eileen M. ; Ahn, Jaimo ; Jan De Beur, Suzanne M ; Li, Ming ; Xu, Meiqi ; McKinlay Gardner, R. J. ; Zasloff, Michael A. ; Whyte, Michael P. ; Levine, Michael A. ; Kaplan, Frederick S. / Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. In: New England Journal of Medicine. 2002 ; Vol. 346, No. 2. pp. 99-106.
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AU - Shore, Eileen M.

AU - Ahn, Jaimo

AU - Jan De Beur, Suzanne M

AU - Li, Ming

AU - Xu, Meiqi

AU - McKinlay Gardner, R. J.

AU - Zasloff, Michael A.

AU - Whyte, Michael P.

AU - Levine, Michael A.

AU - Kaplan, Frederick S.

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N2 - 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 (G sα) 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 haploinsufficiency of GNAS1, provides evidence that imprinting is a regulatory mechanism for GNAS1 expression, and suggests that G sα is a critical negative regulator of osteogenic commitment in nonosseous connective tissues.

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