FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 346:99-106 January 10, 2002 Number 2 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Jüppner, H. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited Related Article PubMed Citation

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_s) 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_s is a critical negative regulator of osteogenic commitment in nonosseous connective tissues.

Source Information

From the Departments of Orthopaedic Surgery (E.M.S., J.A., M.L., M.X., F.S.K.), Genetics (E.M.S., M.A.Z.), and Medicine (F.S.K.), University of Pennsylvania School of Medicine, Philadelphia; the Ilyssa Center for Molecular and Cellular Endocrinology (S.J.B., M.A.L.) and the Departments of Medicine (S.J.B.) and Pediatrics (M.A.L.), Johns Hopkins University School of Medicine, Baltimore; Genetic Health Services, Victoria and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia (R.J.M.G.); and the Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, and the Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis (M.P.W.).

Address reprint requests to Dr. Shore at the Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, 424 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104-6018, or at shore{at}mail.med.upenn.edu.

Full Text of this Article

Related Letters:

GNAS1 Mutations and Progressive Osseous Heteroplasia
Ahmed S. F., Barr D. G.D., Bonthron D. T., Farfel Z., Shore E. M., Kaplan F. S., Levine M. A., Bastepe M., Jüppner H.
Extract | Full Text | PDF  
N Engl J Med 2002; 346:1669-1671, May 23, 2002. Correspondence

This article has been cited by other articles:

• Aydin, C., Aytan, N., Mahon, M. J., Tawfeek, H. A. W., Kowall, N. W., Dedeoglu, A., Bastepe, M. (2009). Extralarge XL{alpha}s (XXL{alpha}s), a Variant of Stimulatory G Protein {alpha}-Subunit (Gs{alpha}), Is a Distinct, Membrane-Anchored GNAS Product that Can Mimic Gs{alpha}. Endocrinology 150: 3567-3575 [Abstract] [Full Text]  
• (2008). Picture of the Month--Diagnosis. Arch Pediatr Adolesc Med 162: 1092-1092 [Full Text]  
• Plagge, A., Kelsey, G., Germain-Lee, E. L (2008). Physiological functions of the imprinted Gnas locus and its protein variants G{alpha}s and XL{alpha}s in human and mouse. J Endocrinol 196: 193-214 [Abstract] [Full Text]  
• Zhao, Y., Ding, S. (2007). A high-throughput siRNA library screen identifies osteogenic suppressors in human mesenchymal stem cells. Proc. Natl. Acad. Sci. USA 104: 9673-9678 [Abstract] [Full Text]  
• Yeon, H. B., Kaplan, F. S., Shore, E. M., Rosenberg, A. E., Jupiter, J. B. (2007). Focal Fibronodular Heterotopic Ossification. A Case Report. JBJS 89: 1329-1336 [Full Text]  
• Frohlich, L. F., Bastepe, M., Ozturk, D., Abu-Zahra, H., Juppner, H. (2007). Lack of Gnas Epigenetic Changes and Pseudohypoparathyroidism Type Ib in Mice with Targeted Disruption of Syntaxin-16. Endocrinology 148: 2925-2935 [Abstract] [Full Text]  
• Liu, S., Quarles, L. D. (2007). How Fibroblast Growth Factor 23 Works. J. Am. Soc. Nephrol. 18: 1637-1647 [Abstract] [Full Text]  
• Gimble, J. M., Katz, A. J., Bunnell, B. A. (2007). Adipose-Derived Stem Cells for Regenerative Medicine. Circ. Res. 100: 1249-1260 [Abstract] [Full Text]  
• Seror, R., Job-Deslandre, C., Kahan, A. (2007). Progressive osseous heteroplasia: a rare case of late onset. Rheumatology (Oxford) 46: 716-717 [Full Text]  
• Long, D. N., McGuire, S., Levine, M. A., Weinstein, L. S., Germain-Lee, E. L. (2007). Body Mass Index Differences in Pseudohypoparathyroidism Type 1a Versus Pseudopseudohypoparathyroidism May Implicate Paternal Imprinting of G{alpha}s in the Development of Human Obesity. J. Clin. Endocrinol. Metab. 92: 1073-1079 [Abstract] [Full Text]  
• Linglart, A., Mahon, M. J., Kerachian, M. A., Berlach, D. M., Hendy, G. N., Juppner, H., Bastepe, M. (2006). Coding GNAS Mutations Leading to Hormone Resistance Impair in Vitro Agonist- and Cholera Toxin-Induced Adenosine Cyclic 3',5'-Monophosphate Formation Mediated by Human XL{alpha}s. Endocrinology 147: 2253-2262 [Abstract] [Full Text]  
• Bastepe, M., Juppner, H. (2005). Pseudohypoparathyroidism, Gs{alpha}, and the GNAS Locus. IBMS BoneKEy 2: 20-32 [Full Text]  
• Weinstein, L. S., Liu, J., Sakamoto, A., Xie, T., Chen, M. (2004). Minireview: GNAS: Normal and Abnormal Functions. Endocrinology 145: 5459-5464 [Abstract] [Full Text]  
• Kaplan, F. S., Glaser, D. L., Hebela, N., Shore, E. M. (2004). Heterotopic Ossification. J Am Acad Orthop Surg 12: 116-125 [Abstract] [Full Text]  
• Freson, K., Jaeken, J., Van Helvoirt, M., de Zegher, F., Wittevrongel, C., Thys, C., Hoylaerts, M. F., Vermylen, J., Van Geet, C. (2003). Functional polymorphisms in the paternally expressed XL{alpha}s and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation. Hum Mol Genet 12: 1121-1130 [Abstract] [Full Text]  
• Bastepe, M., Gunes, Y., Perez-Villamil, B., Hunzelman, J., Weinstein, L. S., Juppner, H. (2002). Receptor-Mediated Adenylyl Cyclase Activation Through XL{alpha}s, the Extra-Large Variant of the Stimulatory G Protein {alpha}-Subunit. Mol. Endocrinol. 16: 1912-1919 [Abstract] [Full Text]  
• Ahmed, S. F., Barr, D. G.D., Bonthron, D. T., Farfel, Z., Shore, E. M., Kaplan, F. S., Levine, M. A., Bastepe, M., Juppner, H. (2002). GNAS1 Mutations and Progressive Osseous Heteroplasia. NEJM 346: 1669-1671 [Full Text]  
• Juppner, H. (2002). The Genetic Basis of Progressive Osseous Heteroplasia. NEJM 346: 128-130 [Full Text]