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Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia.
N Engl J Med. 2002 Jan 10; 346(2):99-106.NEJM

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 (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.

Authors+Show Affiliations

Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia 19104-6018, USA. shore@mail.med.upenn.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11784876

Citation

Shore, Eileen M., et al. "Paternally Inherited Inactivating Mutations of the GNAS1 Gene in Progressive Osseous Heteroplasia." The New England Journal of Medicine, vol. 346, no. 2, 2002, pp. 99-106.
Shore EM, Ahn J, Jan de Beur S, et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med. 2002;346(2):99-106.
Shore, E. M., Ahn, J., Jan de Beur, S., Li, M., Xu, M., Gardner, R. J., Zasloff, M. A., Whyte, M. P., Levine, M. A., & Kaplan, F. S. (2002). Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. The New England Journal of Medicine, 346(2), 99-106.
Shore EM, et al. Paternally Inherited Inactivating Mutations of the GNAS1 Gene in Progressive Osseous Heteroplasia. N Engl J Med. 2002 Jan 10;346(2):99-106. PubMed PMID: 11784876.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. AU - Shore,Eileen M, AU - Ahn,Jaimo, AU - Jan de Beur,Suzanne, AU - Li,Ming, AU - Xu,Meiqi, AU - Gardner,R J McKinlay, AU - Zasloff,Michael A, AU - Whyte,Michael P, AU - Levine,Michael A, AU - Kaplan,Frederick S, PY - 2002/1/11/pubmed PY - 2002/1/25/medline PY - 2002/1/11/entrez SP - 99 EP - 106 JF - The New England journal of medicine JO - N. Engl. J. Med. VL - 346 IS - 2 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 (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. SN - 1533-4406 UR - https://www.unboundmedicine.com/medline/citation/11784876/Paternally_inherited_inactivating_mutations_of_the_GNAS1_gene_in_progressive_osseous_heteroplasia_ L2 - http://www.nejm.org/doi/full/10.1056/NEJMoa011262?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -