Canto Patricia, Söderlund Daniela, Ramón Guillermo, Nishimura Elisa, Méndez Juan Pablo
Research Unit in Developmental Biology, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México, D.F., México.
Am J Med Genet. 2002 Mar 1;108(2):148-52. doi: 10.1002/ajmg.10218.
Inactivating mutations of the luteinizing hormone receptor (LHR) gene in males induce Leydig cell agenesis or hypoplasia, while activating mutations cause testotoxicosis. Recently, it was demonstrated that a somatic heterozygous activating mutation of the LHR gene (Asp578His), limited to the tumor, was the cause of Leydig cell adenomas in three unrelated patients. We describe the molecular study of two unrelated boys with gonadotropin-independent hypersecretion of testosterone due to Leydig cell adenomas. Genomic DNA was extracted from the tumor, the adjacent normal testis tissue, and blood leukocytes. Both individuals exhibited an heterozygous missense mutation, limited only to the tumor, consisting of a guanine (G) to cytosine (C) substitution at codon 578 (GAT to CAT), turning aspartic acid into histidine. The presence of the same mutation in different ethnic groups demonstrates the existence of a mutational hot spot in the LHR gene. Indeed, this mutation occurs at the conserved aspartic acid residue at amino acid 578, where a substitution by glycine is the most common mutation observed in testotoxicosis and where a substitution by tyrosine has been linked to a more severe clinical phenotype where diffuse Leydig cell hyperplasia is found. Our results confirm the fact that somatic activating mutations of gonadotropin receptors are involved in gonadal tumorigenesis.
男性促黄体生成素受体（LHR）基因的失活突变会导致睾丸间质细胞发育不全或发育不良，而激活突变则会引发睾丸中毒症。最近有研究表明，LHR基因的一种体细胞杂合激活突变（Asp578His），仅局限于肿瘤，是三名无血缘关系患者睾丸间质细胞瘤的病因。我们描述了对两名因睾丸间质细胞瘤导致促性腺激素非依赖性睾酮分泌过多的无血缘关系男孩的分子研究。从肿瘤、相邻正常睾丸组织和血液白细胞中提取基因组DNA。两名个体均表现出仅局限于肿瘤的杂合错义突变，该突变由密码子578处的鸟嘌呤（G）到胞嘧啶（C）的替换（GAT到CAT）组成，导致天冬氨酸变为组氨酸。不同种族群体中存在相同突变表明LHR基因存在突变热点。事实上，该突变发生在氨基酸578处保守的天冬氨酸残基上，在睾丸中毒症中最常见的突变是该位点被甘氨酸取代，而被酪氨酸取代则与更严重的临床表型相关，即出现弥漫性睾丸间质细胞增生。我们的结果证实了促性腺激素受体的体细胞激活突变参与性腺肿瘤发生这一事实。
