A NONSENSE MUTATION OF THE HUMAN LUTEINIZING-HORMONE RECEPTOR GENE INLEYDIG-CELL HYPOPLASIA

Leydig cell hypoplasia (LCH) is a form of male pseudohermaphroditism i n which Leydig cell differentiation and testosterone production are im paired, This report describes the first case of a nonsense mutation (A 1635C) in exon 11 of the human luteinizing hormone receptor (hLHR) gen e in two sisters with LCH. This mutation causes loss of function of th e receptor by introducing a stop codon at residue 545 in transmembrane helix 5 of the hLHR. Surface expression of the truncated hLHR (hLHR-t 545) in human embryonic kidney cells stably transfected with cDNA enco ding hLHR-t545 was diminished compared to the wild-type hLHR and hCG-i nduced cAMP accumulation was impaired, These results establish that si ngle base mutations in exon 11 of the hLHR gene can produce inactivati on as well as activation of the hLMR. Furthermore, they demonstrate th at functional domains between transmembrane helix 5 and the C-terminal cytoplasmic tail of the hLHR are required for normal cell surface exp ression of the receptor and signal transduction.