GNAS mutations in Pseudohypoparathyroidism type 1a and related disorders.
GNAS mutations in Pseudohypoparathyroidism type 1a and related disorders.
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DOI：
10.1002/humu.22696
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发表时间：
2015-01
期刊：
影响因子：
3.9
通讯作者：
Thakker, Rajesh V.
中科院分区：
文献类型：
--
作者：
Lemos, Manuel C.;Thakker, Rajesh V.
关键词：
假性甲状旁腺功能减退症1a型（PHP 1a）的特征是由于甲状旁腺激素抵抗引起的低钙血症和高磷血症，与奥尔布赖特遗传性骨营养不良（AHO）的特征相关。PHP 1a由Gs-alpha的母系遗传失活突变引起，Gs-alpha由称为GNAS的复杂印记基因座编码。父系遗传的突变可导致以单纯AHO为特征的假性甲状旁腺功能减退症（PPHP），或以严重异位骨化为特征的进行性骨异型增生（POH）。PHP 1a及其相关疾病的临床方面和分子遗传学与GS-α生殖系突变的343激酶的文献报道一起进行审查。这343个（176个不同的）突变分散在编码GS-α的13个外显子中，包括44.9%的移码突变、28.0%的错义突变、14.0%的无义突变和9.0%的剪接位点突变、3.2%的框内缺失或插入突变以及0.9%的全部或部分基因缺失。移码和其他高度破坏性突变在已报道的37种POH激酶中比在PHP 1a/PPHP激酶中更常见（97.3%vs.68.7%，P < 0.0001）。这种突变更新和相应的基因型-表型数据可能有助于诊断和研究目的，并有助于更好地了解这些复杂的疾病。
Pseudohypoparathyroidism type 1a (PHP1a) is characterized by hypocalcaemia and hyperphosphatemia due to parathyroid hormone resistance, in association with the features of Albright's hereditary osteodystrophy (AHO). PHP1a is caused by maternally inherited inactivating mutations of Gs-alpha, which is encoded by a complex imprinted locus termed GNAS. Paternally inherited mutations can lead either to pseudopseudohypoparathyroidism (PPHP) characterized by AHO alone, or to progressive osseous heteroplasia (POH), characterized by severe heterotopic ossification. The clinical aspects and molecular genetics of PHP1a and its related disorders are reviewed together with the 343 kindreds with Gs-alpha germline mutations reported so far in the literature. These 343 (176 different) mutations are scattered throughout the 13 exons that encode Gs-alpha and consist of 44.9% frameshift, 28.0% missense, 14.0% nonsense, and 9.0% splice-site mutations, 3.2% in-frame deletions or insertions, and 0.9% whole or partial gene deletions. Frameshift and other highly disruptive mutations were more frequent in the reported 37 POH kindreds than in PHP1a/PPHP kindreds (97.3% vs. 68.7%, P < 0.0001). This mutation update and respective genotype–phenotype data may be of use for diagnostic and research purposes and contribute to a better understanding of these complex disorders.
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