title: Mutational analysis of the luteinizing hormone receptor gene in two individuals with Leydig cell tumors.
abstract: 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.
authors.affiliation: Research Unit in Developmental Biology, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México, D.F., México.
authors.forename: Patricia
authors.initials: P
authors.lastname: Canto
authors.forename: Daniela
authors.initials: D
authors.lastname: Söderlund
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ramón
authors.forename: Elisa
authors.initials: E
authors.lastname: Nishimura
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Méndez
mesh_terms: D001483:Base Sequence; D002648:Child; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D007984:Leydig Cell Tumor / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D011974:Receptors, LH / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D011974:Receptors, LH; D004247:DNA