A novel luteinizing hormone receptor mutation in a patient with familial male-limited precocious puberty: Effect of the size of a critical amino acidon receptor activity

Familial male-limited precocious puberty (FMPP) is a form of luteinizing ho rmone-releasing hormone (LHRH)-independent isosexual precocious puberty cau sed! by gain-of-function mutations of the luteinizing hormone/chorionic gon adotropin receptor (hLHR), The most common mutation is 1733 A>G, which caus es substitution of Asp-578 by Gay. In this study, a male infant presented a t the age of 20 months with accelerated sexual development was analyzed for the presence of activating mutations of the hLHR. Analysis of exon 11 of t he hLHR gene by genomic polymerase chain reaction (PCR), asymmetric PCR, an d dideoxy sequencing identified a single base substitution 1734 T>A, which led to the replacement of Asp-578 by Glu. The same mutation was found in th e mother. Expression of the mutated hLHR in HEK 293 cells demonstrated elev ated basal levels of intracellular cAMP in the transfected cells confirming the constitutive activating nature of the mutated hLHR. A possible genotyp e-phenotype relationship of the hLHR mutations was examined by a comparison of the in vitro activities of the hLHRs carrying the Asp578Gly, Asp578Tyr, Asp578Trp, and Asp578Glu mutations in HEK 293 cells. A positive correlatio n between the size of the substituting amino acid and the basal level of in tracellular cAMP of cells expressing the mutated receptor was demonstrated, (C) 1999 Academic Press.