Gonadotropin receptors: from cloning to genetic diseases

The LH/CG receptor was the first member of a novel family of G protein con pled receptors to be cloned. This family also includes FSH and TSH receptor s. These receptors exhibit a seven transmembrane domain characteristic of a ll G protein coupled receptors, but a large extracellular domain involved i n ligand binding and related to leucine-rich glycoproteins is specific of t his family of receptors. Different forms of LH and FSH receptors are physio logically expressed: a mature transmembrane species corresponding to the fu nctional receptor and a high mannose precursor which accumulates inside the cell. Variant for-ms of the LH receptor generated by alternative splicing and lacking transmembrane domain have been isolated. They can potentiate th e full length receptor function. Human LI-I and FS-T receptor genes are bot h localised on chromosome 2p21. The genes are very large (> 70 kpb). Intron s are restricted to the 5' part encoding the extracellular domain of the re ceptor. The intracellular traffic of the LH receptor has been studied by im munoelectron microscopy in Leydig cells and in transfected L cells. The sam e approach was used to study the receptor-mediated transendothelial transfe r of hCG in testicular microvasculature. The physiological polarisation of the FSH receptor has been reproduced in MDCK cells and a basolateral target ing signal identified. Mutagenesis studies gave informations on structure-f unction relationships. Mice with deleted FSH beta and FSH receptor genes ha ve been obtained. Altogether these models help understanding the role of go nadotropins and. their receptors in the ontogenesis and differentiation of gonads.