Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) and Kallmann syndrome (KS) represent two rare phenotypic presentations of humans with hypogonadotropic hypogonadism secondary to GnRH deficiency. KS/nIHH is genetically heterogeneous and is characterized by incomplete penetrance and variable expressivity. Some genetic variants may play the role of modifier alleles or act as second hits, providing an explanation of this phenotypic variability. In addition to the reproductive phenotypes, nIHH and KS subjects also commonly exhibit craniofacial defects. In humans, mutations in GLI3, encoding a transcriptional regulator of sonic hedgehog (Shh) signaling, causes a spectrum of craniofacial defects including a short nose with flat nasal bridge and cleft palate. Gli3 loss-of-function affects the development of the olfactory system: By examining the development of the vomeronasal sensory neurons, terminal nerve and GnRH-1 neurons, in a Gli3 mouse mutant model [Gli3 extra-toe (Xt)], we found: 1) a large reduction in the number of vomeronasal sensory neurons, 2) defective development and routing of the terminal nerve fibers, and 3) nearly complete absence of GnRH-1 neuronal migration to the brain. Notably, only a delay in GnRH-1 neuronal migration was observed in Gli3Xt/WTheterozygous embryos with no obvious differences after birth. Analyzing whole exome data from a large cohort of nIHH/KS probands, we also identified several rare GLI3 variants in humans. Luciferase assays and subcellular localization confirmed complete loss-of-function for one novel GLI3 mutation which was seen in an KS individual who also displayed polydactyly. As a some of the patients carrying rare missense GLI3 variants also harbored heterozygous mutations in other KS/nIHH candidate genes we propose that human GLI3 mutations could play an important modifier role and contribute to the oligogenic nature of KS/nIHH.
18 - 21 May 2019
European Society of Endocrinology