先天性类脂质性肾上腺增生症分子遗传学分析  

Molecular genetic analysis of congenital lipoid adrenal hyperplasia

作　　者：邱文娟[1] 叶军[1] 韩蓓[1,2] 韩连书 顾学范[1] 

机构地区：[1]上海第二医科大学附属新华医院,上海市儿科医学研究所小儿内分泌遗传代谢病研究室,200092 [2]南京儿童医院内分泌科

出　　处：《中华儿科杂志》2004年第8期585-588,i001,共5页Chinese Journal of Pediatrics

摘　　要：目的 探讨先天性类脂质性肾上腺增生症(CLAH)患者发病的分子遗传学机制。方法对1例19岁男性女性化的CLAH患者进行相关内分泌激素水平评价,并提取来自患者及其父母外周血DNA,采用PCR、DNA序列分析、家系分析和限制性内切酶图谱分析等方法对类固醇生成急性调控蛋白(StAR)基因进行分析。结果 患者基础血促肾上腺皮质激素(ACTH)和促性腺激素显著升高,基础血17羟孕酮(17-OHP)、硫酸脱氢表雄酮(DHEAS)及睾酮水平降低,ACTH兴奋试验后17-OHP、DHEAS水平无明显增高。患者StAR基因存在复合杂合突变:外显子3存在以往未报道过的无义突变Q77X,该突变来自父亲并经限制性内切酶图谱分析证实。外显子6存在838delA移码突变,该突变来自母亲。结论 Q77X是StAR基因的一种新突变,Q77X和838delA突变可使StAR功能丧失或减弱而引起CLAH,开展StAR基因分析有助于明确CLAH的诊断。Objective Congenital lipoid adrenal hyperplasia (CLAH) is an autosomal recessive inherited disorder, characterized by deficiency of adrenal and gonadal steroid hormones. Recent studies have shown that mutations in the gene for steroidogenic acute regulatory protein ( StAR) cause this most severe genetic disorder in steroid hormone biosynthesis. StAR is a mitochondrial protein promotes cholesterol transfer from outer mitochondrial membrane to the inner mitochondrial membrane, where the cholesterol serves as a substrate for P450scc and initiates steroidogenesis. So far, more than 30 different mutations in the StAR gene have been found in the patients with CLAH from various ethnic groups. None of CLAH patients in the Chinese population has been previously reported. In the present study we analyzed the StAR gene in a Chinese patient with CLAH. Methods The patient who was a 19-yr-old phenotypic female, has a 46, XY karyotype. Endocrinological evaluation was performed. Genomic DNA samples were abstracted from the bloods of the patient and his parents. Polymerase chain reaction (PCR) , direct DNA sequencing, family analysis and restriction enzyme digestion analysis were used to detect and confirm the mutations of StAR gene. Results Endocrine evaluation of the patient showed extremely elevated basal concentrations of serum ACTH and gonadotropin and minimal concentration of gonadal steroids. An ACTH stimulation test indicated basal serum dehydroepiandrosterone and 17-hydroxyprogesterone were lower than normal detectable range and had no obvious increase after the ACTH stimulation. Automatic sequencing of 7 exons of the StAR gene with the polymerase chain reaction products of the genomic DNA revealed compound heterozygous for a novel nonsense mutation Q77X in exon 3 and the frameshift mutation 838delA in exon 6. The father carried Q77X mutation and the mother carried 838delA mutation. The restriction enzyme site of the Q77X mutation was examined by endonucleotidase Bfa I. Furthermore, this mutation was not found in a serie

关 键 词：先天性类脂质性肾上腺增生症 分子遗传学 内分泌激素 基因突变 

分 类 号：R725.8[医药卫生—儿科]