"Been hit twice": a novel bi-allelic heterozygous mutation in LHCGR.

Abstract

The pituitary and placental glycoprotein hormone receptors belong to the G-protein-coupled receptor (GPCR) superfamily that contains seven transmembrane helices [1, 2]. Of these, the human luteinizing hormone/chorionic gonadotropin receptor (LHCGR) binds two structurally related hormones: luteinizing hormone (LH) and human chorionic gonadotropin (hCG), derived respectively from pituitary gonadotropes and placental syncytial trophoblasts [1, 2]. In the male LHCGRs are expressed primarily on Leydig cells, although their expression in prostate/prostate cell lines has also been reported [1–6]. In the female, LHCGRs are expressed on ovarian granulosa and thecal cells and regulate ovulation, corpus luteum function, and maintenance of pregnancy [1, 2, 7, 8]. Several studies indicate that LHCGRs are also expressed on various non-gonadal human tissues including the female reproductive tract [1, 2, 7–11]. Stimulation of LHCGRs by LH/hCG ligands results in cAMP production and steroidogenesis depending on cell type, ovary developmental stage and physiological context [7, 8, 12]. Various other intracellular signaling pathways are also affected, although much less is clear regarding their in vivo significance [7, 8]. In the adult female, signaling via LHCGRs is primarily required for ovulation. LHCGRs are under a tightly regulated ligand-mediated desensitization pathway that involves an LH receptor binding protein whose molecular identity, mechanism of action and regulation have been extensively studied in recent years [13–15]. A single gene designated LHCGR encodes the LHCGR that is essential for normal gonadal and reproductive function in both sexes [8, 13, 16, 17]. Although initially considered rare, in the past two decades, various mutations and polymorphisms have been identified in the human LHCGR (located on chromosome 2) that consists of 11 exons and 10 introns [18–23]. These include unique SNPs, or deletions, or point mutations identified throughout the LHCGR resulting in a spectrum of fertility/infertility phenotypes including sex reversal [18–23]. In this issue of JARG, Mitri et al., report a novel compound heterozygous mutation in the LHCGR and present interesting clinical phenotypes that manifest in the affected female patient (Mitri et al., A novel compound heterozygous mutation of the luteinizing hormone receptor: implications for fertility, doi:10.1007/s10815-014-0249-5).