Leydig cell hypoplasia due to inactivation of luteinizing hormone receptor by a novel homozygous nonsense truncation mutation in the seventh transmembrane domain.
Inactivating mutations in the LH receptor are the predominant cause for male pseudohermaphroditism in subjects with Leydig cell hypoplasia (LCH). The severity of the mutations, correlates with residual receptor activities. Here, we detail the clinical presentation of one subject with complete male pseudohermaphroditism and LCH. We identify within the proband and her similarly afflicted sibling a homozygous T to G transversion at nucleotide 1836 in exon 11 of the LH/CGR gene. This causes conversion of a tyrosine codon into a stop codon at codon 612 in the seventh transmembrane domain, resulting in a truncated receptor that lacks a cytoplasmic tail. In vitro, in contrast to cells expressing a normal LHR, cells transfected with the mutant cDNA exhibit neither surface binding of radiolabeled hCG nor cAMP generation. In vitro expression under the control of the LHR signal peptide of either a wild type or mutant LHR-GFP fusion protein shows no differences in receptor cellular localization. In conclusion, the in vitro studies suggest that residues in the seventh transmembrane domain and cytoplasmic tail are important for receptor binding and activation without playing a major role in receptor cellular trafficking.