Isolated GnRH deficiency: A disease model serving as a unique prism into the systems biology of the GnRH neuronal network

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

“…The KS phenotype results from the neurodevelopmental failure of GnRH neuronal migration during development and nIGD results from the neuroendocrine failure of GnRH secretion/ action within the hypothalamus (12,13). Whereas most genes exclusively cause either the KS or nIGD forms of the disease, a subset of genes (e.g., FGF8/FGFR1, PROK2/PROKR2) are associated with both KS and nIGD, indicating either (i) two potentially different pathophysiologic sites of actions on the ontogeny of GnRH neurons or (ii) the potential for dissociated effects on the ontogeny of GnRH neurons and olfactory axons, respectively (12,13). Although the initial report by Kim et al (8) implicated CHD7 in both KS and nIGD, subsequent investigators have failed to identify any predicted pathogenic CHD7 RSVs in nIGD (9,16).…”

“…Around 60% of IGD patients also manifest a variety of nonreproductive defects, principally anosmia, which defines Kallmann syndrome (KS), whereas the remainder exhibit a pure nonsyndromic neuroendocrine phenotype, referred to as normosmic IGD (nIGD) (12,13). In KS, a shared migratory defect of GnRH and olfactory axons produces IGD and anosmia, respectively, whereas other defects result from perturbation of other developmental pathways and processes (14).…”

MicroRNA-7a2 suppression causes hypogonadotropism and uncovers signaling pathways in gonadotropes

“…Patients suffering from idiopathic hypogonadotropic hypogonadism (IHH) generally exhibit a defect in either the secretion of GnRH from the hypothalamus and/or its action at the level of the anterior pituitary, such as has been observed in a human and murine model of GnRH deficiency (8). However, this rare clinical entity can also be associated with anosmia, a defect that occurs in approximately 50% to 60% of patients and generally signals a developmental failure in the migration or differentiation of the GnRH neurons in their travels from their embryonic origins in the olfactory placode to their final anatomic destination within the hypothalamus.…”

“Been hit twice”: a novel bi-allelic heterozygous mutation in LHCGR

“…Second, cases of sex reversal resulting in Leydig cell defects that could have been misdiagnosed as androgen-insensitivity could be revisited and genetic screening of these patients for any potential mutations in LHCGR could be undertaken [33]. Third, digenic and oligo-genic mutations in several genes that act in concert are known to cause a variety of human reproductive disorders [33][34][35][36][37]. It is likely that some forms of idiopathic infertility cases could result from heterozygous mutations in one allele of LHCGR and another yet unidentified gene (s).…”

“…It is likely that some forms of idiopathic infertility cases could result from heterozygous mutations in one allele of LHCGR and another yet unidentified gene (s). One could begin to analyze DNA samples from such patients using the emerging high-throughput sequencing approaches [33][34][35][36][37]. Finally, if indeed the 27 bp mutation in LHCGR exon I results in mis-routing and ER trapping of the mutant LHCGRs, attempts to rescue these misfolded/ ER-trapped receptors in vitro [38] and eventually in patients using a pharmacoperone-based therapeutic approach should be feasible [25,39,40].…”