GNAS Spectrum of Disorders

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• 作者：Serap Turan ; Murat Bastepe
• 关键词：GNAS ; Pseudohypoparathyroidism ; Gsα ; Alpha ; subunit of the stimulatory G protein
• 刊名：Current Osteoporosis Reports
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：13
• 期：3
• 页码：146-158
• 全文大小：704 KB
• 参考文献：Papers of particular interest, published recently, have been highlighted as: -Of importance ?-Of major importance1.Blatt C, Eversole-Cire P, Cohn VH, et al. Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human. Proc Natl Acad Sci U S A. 1988;85:7642-6.PubMed Central PubMed
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  4.Ishikawa Y, Bianchi C, Nadal-Ginard B, et al. Alternative promoter and 5' exon generate a novel Gsα mRNA. J Biol Chem. 1990;265:8458-2.PubMed
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• 作者单位：Serap Turan (1)
  Murat Bastepe (2)
  
  1. Pediatric Endocrinology, Marmara University School of Medicine Hospital, Istanbul, Turkey
  2. Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St. Thier 10, Boston, MA, 02114, USA
  
• 刊物主题：Orthopedics; Epidemiology;
• 出版者：Springer US
• ISSN：1544-2241

文摘

The GNAS complex locus encodes the alpha-subunit of the stimulatory G protein (Gsα), a ubiquitous signaling protein mediating the actions of many hormones, neurotransmitters, and paracrine/autocrine factors via generation of the second messenger cAMP. GNAS gives rise to other gene products, most of which exhibit exclusively monoallelic expression. In contrast, Gsα is expressed biallelically in most tissues; however, paternal Gsα expression is silenced in a small number of tissues through as-yet-poorly understood mechanisms that involve differential methylation within GNAS. Gsα-coding GNAS mutations that lead to diminished Gsα expression and/or function result in Albright’s hereditary osteodystrophy (AHO) with or without hormone resistance, i.e., pseudohypoparathyroidism type-Ia/Ic and pseudo-pseudohypoparathyroidism, respectively. Microdeletions that alter GNAS methylation and, thereby, diminish Gsα expression in tissues in which the paternal Gsα allele is normally silenced also cause hormone resistance, which occurs typically in the absence of AHO, a disorder termed pseudohypoparathyroidism type-Ib. Mutations of GNAS that cause constitutive Gsα signaling are found in patients with McCune-Albright syndrome, fibrous dysplasia of bone, and different endocrine and non-endocrine tumors. Clinical features of these diseases depend significantly on the parental allelic origin of the GNAS mutation, reflecting the tissue-specific paternal Gsα silencing. In this article, we review the pathogenesis and the phenotypes of these human diseases.