GNAS1 mutational analysis in pseudohypoparathyroidism
GNAS1 mutational analysis in pseudohypoparathyroidism
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DOI：
10.1046/j.1365-2265.1998.00572.x
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发表时间：
1998-10-01
影响因子：
3.2
通讯作者：
Thakker, RV
中科院分区：
文献类型：
--
作者：
Ahmed, SF;Dixon, PH;Thakker, RV
GNAS1基因位于20q13.11染色体上，编码刺激gtp结合蛋白的α亚基，已在Ia型假性甲状旁腺功能减退症（PHPIa）和假性甲状旁腺功能减退症（PPHP）患者中发现突变，我们开展了研究以确定GNAS1突变的患病率，并探索更快速检测的方法。方法采用单链构象多态性（SSCP）和DNA序列分析方法，对13个非亲缘关系家族（8个同时患有PHPIa和PPHP患者，5个仅患有PPHP患者）进行2-13外显子1050碱基对（bp）区域GNAS1突变的检测，结果8个PHPIa家族中有4个家族检测到GNAS1突变。这些突变包括：两个家族中的两个新的从头错义突变（Pro115Ser和Glu259Val），以及两个不相关家族中相同的密码子189和190的4 bp缺失导致移码。这些结果扩大了与该疾病相关的GNAS1突变谱，证实了涉及密码子189和190的突变热点的存在，发现SSCP分析是一种特异性和敏感的方法，检测到所有4个突变，GNAS1突变未在任何PPHP家族中检测到。结论假性甲状旁腺功能低下似乎是一个异质性群体，GNAS1突变形成了大约50%的假性甲状旁腺功能低下la型家族的分子病因。这种突变可以通过单链构象多态性可靠地识别，这将有助于补充一些患者及其家庭的临床评估，特别是当疾病可能不完全渗透时。
OBJECTIVE Mutations of the GNAS1 gene, which is located on chromosome 20q13.11 and encodes the alpha-subunit of the stimulatory GTP-binding protein, have been identified in patients with pseudohypoparathyroidism type Ia (PHPIa) and pseudopseudohypoparathyroidism (PPHP), We have undertaken studies to determine the prevalence of GNAS1 mutations and to explore methods for their more rapid detection.METHODS Thirteen unrelated families (8 with PHPIa and PPHP patients, and 5 with PPHP patients only) were investigated for GNAS1 mutations in the 1050 base-pair (bp) region spanning exons 2-13 by single-stranded conformational polymorphism (SSCP) and DNA sequence analysis,RESULTS GNAS1 mutations were detected in 4 of the 8 families with PHPIa patients. These consisted of: two novel de novo missense mutations (Pro115Ser and Glu259Val) in two families and an identical 4 bp deletion of codons 189 and 190 resulting in a frameshift in two unrelated families. These results expand the spectrum of GNAS1 mutations associated with this disorder and confirm the presence of a mutational hot-spot involving codons 189 and 190, SSCP analysis was found to be a specific and sensitive method that detected all 4 mutations, GNAS1 mutations were not detected in any of the PPHP only families.CONCLUSIONS The pseudohypoparathyroid disorders appear to represent a heterogeneous group with GNAS1 mutations forming the molecular aetiology in approximately 50% of pseudohypoparathyroidism type la families. Such mutations can be reliably identified by single-stranded conformational polymorphism and this will help to supplement the clinical evaluation of some patients and their families, particularly as the disease may not be fully penetrant.