A GNAS1 imprinting defect in pseudohypoparathyroidism type IB
A GNAS1 imprinting defect in pseudohypoparathyroidism type IB
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DOI：
10.1172/jci10431
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发表时间：
2000-11-01
影响因子：
15.9
通讯作者：
Weinstein, LS
中科院分区：
文献类型：
--
作者：
Liu, J;Litman, D;Weinstein, LS
IB型假性甲状旁腺功能减退症（PHPIB）的特征是肾对甲状旁腺激素（PTH）的抵抗，并且没有其他内分泌或身体异常。家族性PHPIB已定位于20q13，靠近GNAS1，其编码G（s）α，受体刺激cAMP产生所需的G蛋白α亚基。然而，PHPIB患者的血细胞中G（s）α功能正常，排除了G（s）α编码区内的突变。在小鼠中，G（s）α仅从肾近端小管（PTH作用的位点）中的母体等位基因表达，但在大多数其他组织中双等位基因表达。对奥尔布赖特遗传性骨营养不良患者的研究表明，人类也有类似的G（s）α印记模式。在这里，我们确定了一个区域的G（S）α启动子的上游，通常是甲基化的母亲等位基因和非甲基化的父亲等位基因，但这是非甲基化的两个等位基因在所有13 PHPIB患者的研究。在该区域内是替代启动子和第一外显子（外显子1A），产生通常仅从父系等位基因表达的转录物，但在PHPIB患者中双等位基因表达。因此，PHPIB与两个等位基因上外显子1A区域的父系特异性印迹模式相关，这可能导致肾近端小管中G（s）α表达降低。我们认为外显子1A印记的缺失是PHPIB的原因。
Pseudohypoparathyroidism type IB (PHPIB) is characterized by renal resistance to parathyroid hormone (PTH) and the absence of other endocrine or physical abnormalities. Familial PHPIB has been mapped to 20q13, near GNAS1, which encodes G(s)alpha, the G protein alpha -subunit required for receptor-stimulated cAMP generation. However, G(s)alpha function is normal in blood cells from PHPIB patients, ruling out mutations within the G(s)alpha coding region. In mice G(s)alpha is expressed only from the maternal allele in renal proximal tubules (the site of PTH action) but is biallelically expressed in most other tissues. Studies in patients with Albright hereditary osteodystrophy suggest a similar G(s)alpha imprinting pattern in humans. Here we identify a region upstream of the G(s)alpha promoter that is normally methylated on the maternal allele and unmethylated on the paternal allele, but that is unmethylated on both alleles in all 13 PHPIB patients studied. Within this region is an alternative promoter and first exon (exon 1A), generating transcripts that are normally expressed only from the paternal allele, but that are biallelically expressed in PHPIB patients. Therefore, PHPIB is associated with a paternal-specific imprinting pattern of the exon 1A region on both alleles, which may lead to decreased G(s)alpha expression in renal proximal tubules. We propose that loss of exon 1A imprinting is the cause of PHPIB.