Reading beyond the sequence- the plasticity of the LH/CG-LH receptor system
Joerg Gromoll, Nina Kossack, Annette Richter-Unruh & Manuela Simoni
Male sexual development and masculinization are triggered by two hormones, CG and LH. While CG, produced by the trophoblasts during pregnancy, is essential for normal development of male secondary sex organs, pituitary LH is indispensable for virilization and initiation and maintenance of spermatogenesis. Both hormones exert their action via the LH receptor (LHR) expressed in the Leydig cells by stimulating testosterone biosynthesis. This two hormone/one receptor system is exclusive to the human and certain primates, indicating a very recent evolutionary event i.e. the formation of two reproductive hormones. We recently could show that this hormone-receptor system displays unexpected flexibility with respect to the functional role of its ligands and the receptor type. In New World monkeys the pituitary LH synthesis is inactivated and its role been overtaken by CG, which acts both as a reproductive and a pregnancy hormone in this primate species. Moreover, and possibly as a consequence of this hormone inactivation, the LHR in these monkeys naturally lacks exon 10, therefore giving rise to a new subclass of receptors named LHR type 2. The lack of exon 10 is caused by three unique point mutations in the genomic region of exon 10, which lead to constitutive exon skipping. This molecular mechanism represents a paradigm for alternative splicing of glycoprotein hormone receptors.
In addition to the remarkable interchangeability of LH and CG with respect to reproductive functions and the LHR type 2, we identified a new, primate-specific, regulatory exon within the LHR gene. This exon resembles characteristics of a composite exon acting either as terminal exon, giving rise a putative truncated LHR protein consisting only of major parts of the extracellular domain, or can act as an additional internal exon of the full mature LHR transcript. In this case, due to the presence of premature termination codons within the exon, the LHR transcripts are a potential target for non-sense mediated decay of LHR transcripts. Mutations within this novel exon result in disorders of male sexual development.