Abstract
Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range of conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed to discover important underlying regulators of self-limited delayed puberty through interrogation of GnRH pathways. Whole exome sequencing (WES) data consisting of 193 individuals, from 100 families with self-limited delayed puberty, was analysed using a virtual panel of genes related to GnRH development and function (n = 12). Five rare predicted deleterious variants in Coiled-Coil Domain Containing 141 (CCDC141) were identified in 21 individuals from 6 families (6% of the tested cohort). Homology modeling predicted all five variants to be deleterious. CCDC141 mutant proteins showed atypical subcellular localization associated with abnormal distribution of acetylated tubulin, and expression of mutants resulted in a significantly delayed cell migration, demonstrated in transfected HEK293 cells. These data identify mutations in CCDC141 as a frequent finding in patients with self-limited delayed puberty. The mis-localization of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with heterozygous defects potentially impacting the timing of puberty.
Highlights
Puberty is an intricate biological process, which results from the activation of the hypothalamic-pituitary-gonadal (HPG) axis
We explored whether genetic controllers of pubertal timing can be discovered by genomic analysis in familial self-limited delayed puberty, by focusing on genes in pathways related to development of the gonadotropin-releasing hormone (GnRH) network previously reported to cause idiopathic hypogonadotropic hypogonadism (IHH)
Only a small number of underlying genetic regulators of self-limited delayed puberty have been identified and most of them are related to GnRH biology, including GnRH neuronal migration, maturation and function[5,12,14]
Summary
Puberty is an intricate biological process, which results from the activation of the hypothalamic-pituitary-gonadal (HPG) axis. Before this axis is established, GnRH neurons undergo a complex migratory journey from the nasal placode into the hypothalamus during fetal life. An elaborate interaction of paracrine signaling networks influences both this migratory process and future GnRH secretion[1,2] Derangement of this migratory activity has been reported to cause abnormalities of pubertal development, including idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty[3,4,5]. Several underlying mechanisms have been identified which lead to self-limited delayed puberty, including defects of GnRH neuronal development[5,12], maturation and function[13], upstream controllers of the HPG axis[14] and regulators of energy homeostasis[15]
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