Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia
Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia
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DOI：
10.1056/nejmoa011262
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发表时间：
2002-01-10
影响因子：
158.5
通讯作者：
Kaplan, FS
中科院分区：
文献类型：
--
作者：
Shore, EM;Ahn, J;Kaplan, FS
背景进行性骨发育不全（Progressive osteous heteroplasia，POH）是一种常染色体显性遗传病，其特征是儿童期广泛的皮肤骨化，随后骨骼肌和深部结缔组织广泛异位骨化，致残。偶尔报告轻度异位骨化的奥尔布赖特遗传性骨营养不良（AHO）和最近的两个报告与AHO患者谁有广泛的异位骨化提出了一个共同的遗传基础，这两种疾病。AHO是由GNAS 1基因中的杂合失活突变引起的，该突变导致腺苷酸环化酶的刺激性G蛋白（G（s）α）的α亚基的表达或功能降低。使用聚合酶链反应扩增GNAS 1外显子和外显子-结果在18例散发性或家族性POH先证者中，有13例存在杂合性GNAS 1失活突变。POH中的缺陷等位基因完全从父亲那里遗传，这一结果与GNAS 1的印记模型一致。直接的证据表明，相同的突变可以导致POH或AHO内观察到一个单一的家庭，其中的表型与父母的突变等位基因origination.Conclusions父系遗传失活GNAS 1突变导致POH。这一发现扩展了GNAS 1单倍不足的表型范围，提供了证据表明印记是GNAS 1表达的调节机制，并表明G，a是非骨结缔组织中成骨承诺的关键负调节因子。（N Engl J Med 2002;346：99-106.）版权所有（C）2002马萨诸塞州医学会。
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)alpha) 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,a is a critical negative regulator of osteogenic commitment in nonosseous connective tissues. (N Engl J Med 2002;346:99-106.) Copyright (C) 2002 Massachusetts Medical Society.