Hayward B E, Moran V, Strain L, Bonthron D T
Human Genetics Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15475-80. doi: 10.1073/pnas.95.26.15475.
The GNAS1 gene encodes the alpha subunit of the guanine nucleotide-binding protein Gs, which couples signaling through peptide hormone receptors to cAMP generation. GNAS1 mutations underlie the hormone resistance syndrome pseudohypoparathyroidism type Ia (PHP-Ia), so the maternal inheritance displayed by PHP-Ia has raised suspicions that GNAS1 is imprinted. Despite this suggestion, in most tissues Gsalpha is biallelically encoded. In contrast, the large G protein XLalphas, also encoded by GNAS1, is paternally derived. Because the inheritance of PHP-Ia predicts the existence of maternally, rather than paternally, expressed transcripts, we have investigated the allelic origin of other mRNAs derived from GNAS1. We find this gene to be remarkable in the complexity of its allele-specific regulation. Two upstream promoters, each associated with a large coding exon, lie only 11 kb apart, yet show opposite patterns of allele-specific methylation and monoallelic transcription. The more 5' of these exons encodes the neuroendocrine secretory protein NESP55, which is expressed exclusively from the maternal allele. The NESP55 exon is 11 kb 5' to the paternally expressed XLalphas exon. The transcripts from these two promoters both splice onto GNAS1 exon 2, yet share no coding sequences. Despite their structural unrelatedness, the encoded proteins, of opposite allelic origin, both have been implicated in regulated secretion in neuroendocrine tissues. Remarkably, maternally (NESP55), paternally (XLalphas), and biallelically (Gsalpha) derived proteins all are produced by different patterns of promoter use and alternative splicing of GNAS1, a gene showing simultaneous imprinting in both the paternal and maternal directions.
GNAS1基因编码鸟嘌呤核苷酸结合蛋白Gs的α亚基，该蛋白通过肽激素受体将信号传导与环磷酸腺苷（cAMP）的生成偶联起来。GNAS1突变是Ia型假性甲状旁腺功能减退症（PHP-Ia）这种激素抵抗综合征的基础，因此PHP-Ia所表现出的母系遗传引发了人们对GNAS1基因印记的怀疑。尽管有此推测，但在大多数组织中，Gsα是由双等位基因编码的。相比之下，同样由GNAS1基因编码的大G蛋白XLαs则是父源的。由于PHP-Ia的遗传模式预示着存在母系而非父系表达的转录本，我们研究了源自GNAS1的其他mRNA的等位基因起源。我们发现该基因在其等位基因特异性调控的复杂性方面十分显著。两个上游启动子，每个都与一个大的编码外显子相关联，它们仅相距11 kb，但却表现出相反的等位基因特异性甲基化和单等位基因转录模式。这些外显子中更靠近5'端的那个编码神经内分泌分泌蛋白NESP55，它仅从母本等位基因表达。NESP55外显子位于父本表达的XLαs外显子的5'端11 kb处。来自这两个启动子的转录本都剪接到GNAS1外显子2上，但没有共享的编码序列。尽管它们在结构上不相关，但源自相反等位基因的编码蛋白都与神经内分泌组织中的分泌调节有关。值得注意的是，母源（NESP55）、父源（XLαs）和双等位基因（Gsα）来源的蛋白都是通过GNAS1基因不同的启动子使用模式和可变剪接产生的，该基因在父系和母系方向上同时存在印记现象。
