MUTATION IN THE GENE ENCODING THE STIMULATORY G-PROTEIN OF ADENYLATE-CYCLASE IN ALBRIGHTS HEREDITARY OSTEODYSTROPHY
MUTATION IN THE GENE ENCODING THE STIMULATORY G-PROTEIN OF ADENYLATE-CYCLASE IN ALBRIGHTS HEREDITARY OSTEODYSTROPHY
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DOI：
10.1056/nejm199005173222002
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发表时间：
1990-05-17
影响因子：
158.5
通讯作者：
LEVINE, MA
中科院分区：
文献类型：
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作者：
PATTEN, JL;JOHNS, DR;LEVINE, MA
Albright遗传性骨营养不良是一种常染色体显性疾病，其特征在于身材矮小、短指（趾）畸形、皮下骨化和α-半乳糖苷酶功能表达降低。刺激性G蛋白的亚基（Gs α）腺苷酸环化酶，这是必要的行动甲状旁腺和其他激素使用环AMP作为细胞内的第二信使。我们发现了一种独特的Ga α来自两个具有Albright遗传性骨营养不良和降低的Gs α的相关患者的红细胞中的蛋白质。生物活性GS α.变体被羧基末端特异性的Gs α识别。抗血清，但不能用特异于GS α氨基末端的多克隆抗血清。为了研究这种结构异常的GS α的分子基础。蛋白质，我们研究了GS α。通过限制性内切酶分析确定基因。当消化NcoI时，来自两个患者的DNA具有异常的限制性片段模式，这与一个GS α的外显子1中NcoI限制性位点的缺失一致。等位基因扩增包括GS α的外显子1的260个碱基对区域。基因和扩增的DNA的直接测序揭示了在一个GS α中位置+1的A到G的转变。两个病人的等位基因该突变将起始密码子aTG（甲硫氨酸）转化为gTG（缬氨酸），阻断正常位点的翻译起始。异常GS α的翻译信使RNA将导致截短的GS α的合成。缺少氨基末端的分子。我们的结论是，在至少一些患者的Albright's遗传性骨营养不良，这种疾病是由一个单一的碱基取代的GS α。基因，因此是由于遗传突变的人G蛋白。
Albright''s hereditary osteodystrophy is an autosomal dominant disorder characterized by a short stature, brachydactyly, subcutaneous ossifications, and reduced expression of function of the .alpha. subunit of the stimulatory G protein (Gs.alpha.) of adenylate cyclase, which is necessary for the action of parathyroid and other hormones that use cyclic AMP as an intracellular second messenger. We identified a unique Ga.alpha. protein in erythrocytes from two related patients with Albright''s hereditary osteodystrophy and reduced Gs.alpha. bioactivity. The Gs.alpha. variant was recognized by a carboxyl terminal-specific Gs.alpha. antiserum but not by polyclonal antiserums specific for the amino terminus of Gs.alpha.. To investigate the molecular basis for this structurally abnormal Gs.alpha. protein, we studied the Gs.alpha. gene by restriction-endonuclease analysis. DNA from the two patients had an abnormal restriction-fragment pattern when digested Ncol, which was consistent with loss of an Ncol restriction site in exon 1 of one Gs.alpha. allele. Amplification of a 260-base-pair region that includes exon 1 of the Gs.alpha. gene and direct sequencing of the amplified DNA revealed an A-to-G transition of position + 1 in one of Gs.alpha. allele from each of the two patients. This mutation converts the initiator aTG (methionine) codon to gTG (valine), blocking initiation of translation at the normal site. Translation of the abnormal Gs.alpha. messenger RNA would result in the synthesis of a truncated Gs.alpha. molecule lacking the amino terminus. We conclude that in at least some patients with Albright''s hereditary osteodystrophy, the disease is caused by a single-base substitution in the Gs.alpha. gene and is thus due to an inherited mutation in a human G protein.