Whole exome sequencing identifies deleterious rare variants in CCDC141 in familial self-limited delayed puberty

Tansit Saengkaew; Gerard Ruiz-Babot; Alessia David; Alessandra Mancini; Katia Mariniello; Claudia P Cabrera; Michael R Barnes; Leo Dunkel; Leonardo Guasti; Sasha R Howard

doi:10.1038/s41525-021-00274-w

Whole exome sequencing identifies deleterious rare variants in CCDC141 in familial self-limited delayed puberty

NPJ Genom Med. 2021 Dec 20;6(1):107. doi: 10.1038/s41525-021-00274-w.

Authors

Affiliations

¹ Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
² Endocrinology Unit, Department of Paediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.
³ Department of Life Sciences, Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London, UK.
⁴ Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁵ NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁶ Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. s.howard@qmul.ac.uk.

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.

Abstract

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