IDENTIFICATION OF A MUTATION IN THE GENE ENCODING THE ALPHA-SUBUNIT OF THE STIMULATORY G-PROTEIN OF ADENYLYL CYCLASE IN MCCUNE-ALBRIGHT SYNDROME
IDENTIFICATION OF A MUTATION IN THE GENE ENCODING THE ALPHA-SUBUNIT OF THE STIMULATORY G-PROTEIN OF ADENYLYL CYCLASE IN MCCUNE-ALBRIGHT SYNDROME
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DOI：
10.1073/pnas.89.11.5152
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发表时间：
1992-06-01
影响因子：
11.1
通讯作者：
LEVINE, MA
中科院分区：
文献类型：
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作者：
SCHWINDINGER, WF;FRANCOMANO, CA;LEVINE, MA
McCune-Albright综合征（MAS）的特征是多骨纤维异常增殖症、内分泌损伤和多种内分泌疾病，包括性早熟、甲状腺功能亢进、皮质醇增多症、生长激素过量和高泌乳素血症。在MAS中观察到的多种代谢异常都涉及细胞，这些细胞通过激活对腺苷酸敏感的腺苷酸环化酶系统（EC 4.6.1.1）对细胞外信号作出反应。已在一部分人生长激素分泌型垂体肿瘤和人甲状腺肿瘤中发现了导致G（s）α（刺激腺苷酸环化酶活性的鸟嘌呤核苷酸结合调节蛋白）组成性激活的突变。我们在这里报告的鉴定基因编码G（S）α在MAS患者的突变。变性梯度凝胶电泳用于分析包括G（s）α基因外显子8或外显子9的扩增DNA片段。在1例MAS受试者中，在编码G（s）α的两个等位基因之一的外显子8中发现了G至A的转换。该单碱基取代导致成熟G（s）α蛋白的位置201处的精氨酸被组氨酸取代。扩增DNA的半定量分析表明，突变体等位基因是普遍低于野生型等位基因在外周血白细胞和皮肤中存在的水平非常低。这些研究结果支持了以前的论点，即节段性分布和可变表达的皮肤，骨骼和内分泌表现的MAS反映了一个潜在的躯体镶嵌。此外，这些结果表明，MAS的分子基础是G（s）α的合子后突变，导致腺苷酸环化酶的组成性激活。
McCune-Albright syndrome (MAS) is characterized by polyostotic fibrous dysplasia, cafe-au-lait lesions, and a variety of endocrine disorders, including precocious puberty, hyperthyroidism, hypercortisolism, growth hormone excess, and hyperprolactinemia. The diverse metabolic abnormalities seen in MAS share the involvement of cells that respond to extracellular signals through activation of the hormone-sensitive adenylyl cyclase system (EC 4.6.1.1). Mutations that lead to constitutive activation of G(s)alpha, the guanine nucleotide-binding regulatory protein that stimulates adenylyl cyclase activity, have been identified in a subset of human growth hormone-secreting pituitary tumors and human thyroid tumors. We report here the identification of a mutation in the gene encoding G(s)alpha in a patient with MAS. Denaturing gradient gel electrophoresis was used to analyze amplified DNA fragments including exon 8 or exon 9 of the G(s)alpha gene. In one subject with MAS a G-to-A transition was found in exon 8 of one of the two alleles encoding G(s)alpha. This single-base substitution results in the replacement of arginine by histidine at position 201 of the mature G(s)alpha protein. Semiquantitative analysis of amplified DNA indicated that the mutant allele was less prevalent than the wild-type allele in peripheral leukocytes and was present in very low levels in skin. These findings support the previous contention that the segmental distribution and variable expression of the cutaneous, skeletal, and endocrine manifestations of MAS reflect an underlying somatic mosaicism. Further, these results suggest that the molecular basis of MAS is a postzygotic mutation in G(s)alpha that causes constitutive activation of adenylyl cyclase.