An update on the clinical and molecular characteristics of pseudohypoparathyroidism.
An update on the clinical and molecular characteristics of pseudohypoparathyroidism.
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DOI：
10.1097/med.0b013e32835a255c
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发表时间：
2012-12
期刊：
影响因子：
--
通讯作者：
Levine MA
中科院分区：
文献类型：
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作者：
Levine MA
为读者提供一个回顾当代文献描述假性甲状旁腺功能低下（PHP）的分子病理生物学的不断发展的认识。PHP 1型的特征反映了GNAS基因的印迹，该基因编码异三聚体G蛋白（Gαs）的α亚基，该基因将七螺旋受体偶联到腺苷酸环化酶的激活中。g - αs的转录在大多数细胞中是双等位基因，但在某些组织（如近端肾小管、甲状腺、垂体生长斜体、性腺）中主要来自母体等位基因。PHP 1a患者在母体GNAS等位基因编码Gαs的外显子内存在杂合突变，而PHP 1b患者在GNAS位点存在甲基化缺陷，从而减少母体等位基因Gαs的转录。在php1a和php1b中，父本印迹Gαs导致对甲状旁腺激素和TSH的抗性。虽然短指是PHP 1a的特征，但它有时也存在于PHP 1b患者中。分子研究证实了PHP 1a和PHP 1b之间的区别，它们具有不同的机制来解释g - αs缺陷。这两种PHP 1型之间的临床重叠可能是由于特定细胞类型中表达的Gαs活性水平不同。
To provide the reader with a review of contemporary literature describing the evolving understanding of the molecular pathobiology of pseudohypoparathyroidism (PHP). The features of PHP type 1 reflect imprinting of the GNAS gene, which encodes the α subunit of the heterotrimeric G protein (Gαs) that couples heptahelical receptors to activation of adenylyl cyclase. Transcription of Gαs is biallelic in most cells, but is primarily from the maternal allele in some tissues (e.g. proximal renal tubules, thyroid, pituitary somatotropes, gonads). Patients with PHP 1a have heterozygous mutations within the exons of the maternal GNAS allele that encode Gαs, whereas patients with PHP 1b have methylation defects in the GNAS locus that reduce transcription of Gαs from the maternal allele. In both PHP 1a and PHP 1b, paternal imprinting of Gαs leads to resistance to parathyroid hormone and TSH. Although brachydactyly is characteristic of PHP 1a, it is sometimes present in patients with PHP 1b. Molecular studies enable a distinction between PHP 1a and PHP 1b, with different mechanisms accounting for Gαs deficiency. Clinical overlap between these two forms of PHP type 1 is likely due to the variable levels of Gαs activity expressed in specific cell types.