Endocrine Abstracts

Puberty is a fascinating transition period in the mammalian lifespan, but the biological control of pubertal timing remains poorly understood. Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network have been shown to be responsible for disorders of pubertal timing, in a spectrum of conditions ranging from idiopathic hypogonadotropic hypogonadism (IHH) to self-limited delayed puberty. We hypothesized that important regulators of pubertal timing could be identified through interrogation of genetic defects in GnRH pathways in patients with pubertal delay. We analyzed whole exome sequencing data from 197 individuals, from 100 pedigrees from our cohort with familial self-limited delayed puberty. We applied a virtual panel of gene pathways related to GnRH development and function to filter the dataset returned from this whole exome sequencing study (n = 12). From this analysis we identified six rare predicted deleterious variants in the gene Coiled-Coil Domain Containing 141 (CCDC141) in 26 individuals from 8 families. Previous studies reported that homozygous or compound heterozygous mutations of CCDC141 cause Kallmann syndrome and IHH, due to impaired GnRH neuronal migration. All probands who were found to carry heterozygous missense variants showed typical clinical manifestations of SLDP. Homology modelling predicted the pathogenicity of all 6 of these variants. Our in vitro studies demonstrated that CCDC141 mutant proteins have atypical subcellular localisation associated with abnormal distribution of acetylated tubulin. Moreover, expression of mutant proteins in a cellular assay resulted in a significantly delayed cell migration. These data identify mutations in CCDC141 as a frequent cause of SLDP. The mis-localisation of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with defects impacting the timing of puberty.