RARE BONE DISEASE ( CB LANGMAN AND E SHORE , SECTION EDITORS ) GNAS Spectrum of Disorders
RARE BONE DISEASE ( CB LANGMAN AND E SHORE , SECTION EDITORS ) GNAS Spectrum of Disorders
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发表时间：
2015
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通讯作者：
S. Turan;M. Bastepe
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作者：
S. Turan;M. Bastepe
GNAS复合物位点编码刺激G蛋白（Gsα）的α亚基，Gsα是一种普遍存在的信号蛋白，通过产生第二信使cAMP介导许多激素、神经递质和旁分泌/自分泌因子的作用。GNAS产生其他基因产物，其中大多数只表现为单等位基因表达。相反，Gsα在大多数组织中双等位表达；然而，在少数组织中，父系Gsα的表达是通过涉及GNAS内差异甲基化的尚不清楚的机制被沉默的。编码Gsα的GNAS突变导致Gsα表达和/或功能降低，导致Albright 's遗传性骨营养不良（who）伴或不伴激素抵抗，即ia /Ic型假性甲状旁腺功能减退症和假性甲状旁腺功能减退症。在父本gsa α等位基因通常沉默的组织中，改变GNAS甲基化并因此减少gsa α表达的微缺失也会引起激素抗性，这种抗性通常发生在who的ab基因中，并被称为伪性甲状旁腺功能低下- ib型。GNAS突变可引起组成性gsa α信号转导，在McCune-Albright综合征、骨纤维性发育不良以及各种内分泌和非内分泌肿瘤患者中均有发现。这些疾病的临床特征在很大程度上取决于GNAS突变的亲本等位基因来源，反映了组织特异性的父本gsa α沉默。在本文中，我们综述了这些人类疾病的发病机制和表型。
The GNAS complex locus encodes the alphasubunit 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 secondmessenger 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 pseudopseudohypoparathyroidism, 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 typicall y i n t he ab sence o f AHO, a d i so rde r t e rmed 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 tissuespecific paternal Gsα silencing. In this article, we review the pathogenesis and the phenotypes of these human diseases.