AI Article Synopsis
- Developmental issues in the GnRH neuronal network can lead to conditions like idiopathic hypogonadotropic hypogonadism and delayed puberty, prompting research into regulatory mechanisms of self-limited delayed puberty.
- The study analyzed whole exome sequencing data from 193 individuals and found rare mutations in the CCDC141 gene in 6% of those tested, suggesting a link to delayed puberty.
- The identified mutations in CCDC141 caused abnormal cellular behavior related to tubulin, indicating that defective CCDC141 could disrupt GnRH neuronal migration and influence the timing of puberty.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688425 | PMC |
| http://dx.doi.org/10.1038/s41525-021-00274-w | DOI Listing |
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