A HOMOZYGOUS MUTATION IN THE LUTEINIZING-HORMONE RECEPTOR CAUSES PARTIAL LEYDIG-CELL HYPOPLASIA - CORRELATION BETWEEN RECEPTOR ACTIVITY ANDPHENOTYPE

Leydig cell hypoplasia (LCH) is characterized by a decreased response of the Leydig cells to LH. As a result, patients with this syndrome di splay aberrant male development ranging from complete pseudohermaphrod itism to males with micropenis but with otherwise normal sex character istics. We have evaluated three brothers with a mild form of LCH. Anal ysis of their LH receptor (LHR) gene revealed a homozygous missense mu tation resulting in a substitution of a lysine residue for a isoleucin e residue at position 625 of the receptor. In vitro analysis of this m utant LHR, LHR(I625K), in HEK293 cells indicated that the signaling ef ficiency was significantly impaired, which explains the partial phenot ype. We have compared this mutant LHR to two other mutant LHRs, LHR(A5 93P) and LHR(S616Y), identified in a complete and partial LCH patient, respectively. Although the ligand-binding affinity for all three muta nt receptors was normal, the hormonal response of LHR(A593P) was compl etely absent and that of LHR(S616Y) and LHR(I625K) was severely impair ed. Low cell surface expression explained the reduced response of LHR( S616Y), while for LHR(I625K) this diminished response was due to a com bination of low cell surface expression and decreased coupling efficie ncy. For LHR(A593P), the absence of a reduced response resulted from b oth poor cell surface expression and a complete deficiency in coupling . Our experiments further show a clear correlation between the severit y of the clinical phenotype of patients and overall receptor signal ca pacity, which is a combination of cell surface expression and coupling efficiency.