A novel inactivating mutation of the LH/chorionic gonadotrophin receptor with impaired membrane trafficking leading to Leydig cell hypoplasia type 1.

OBJECTIVE

The LH/chorionic gonadotrophin receptor (LHCGR) is a G protein-coupled receptor (GPCR) that plays a central role in male sexual differentiation, regulation of ovarian follicular maturation, ovulation and maintenance of corpus luteum and pregnancy, as well as maintenance of testicular testosterone production. Mutations in the LHCGR gene are very rare. The aim of this work was to study the clinical and molecular characteristics of a rare familial LHCGR mutation.

METHODS

Five affected members of a family, including a phenotypically female, but genotypically male (46,XY), patient with Leydig cell hypoplasia type 1 and four genotypically female siblings with reproductive abnormalities, were studied genetically. Cell trafficking studies as well as signalling studies of mutated receptor were performed.

RESULTS

The five affected patients were all homozygous for a novel mutation in the LHCGR gene, a deletion of guanine in position 1850 (1850delG). This resulted in a frameshift affecting most of the C-terminal intracellular domain. In vitro studies demonstrated that the 1850delG receptor was completely incapable of transit to the cell membrane, becoming trapped within the endoplasmic reticulum. This could not be rescued by small-molecule agonist treatment or stimulated intracellularly by co-expression of a yoked human chorionic gonadotrophin.

CONCLUSIONS

This novel LHCGR mutation leads to complete inactivation of the LHCGR receptor due to trafficking and signalling abnormalities, which improves our understanding of the impact of the affected structural domain on receptor trafficking and function.