ESPE Yearbook of Paediatric Endocrinology

NPJ Genom Med. 2021 Dec 20;6(1):107. doi: 10.1038/s41525-021-00274-w. PMID: 34930920https://www.nature.com/articles/s41525-021-00274-w

Brief Summary: This cross-sectional study describes the genetic data of a cohort of patients with self-limited delayed puberty, finding a high prevalence of CCDC141 gene mutations. Using in silico and cellular models, the authors identified a role for CCDC141 mutants in delayed puberty likely caused by abnormal cell migration.

Self-limited delayed puberty (SLDP) is the most common cause of delayed puberty (DP)[1][2]. A family history of DP is frequently reported, with an autosomal dominant transmission and variable penetrance [3]. Only a small number of genes have been identified and are mostly associated with the GnRH network. This study evaluated the genetic data of a cohort of familial SLDP patients and explored the pathophysiological basis of identified mutations.

Whole exome sequencing data from 193 individuals (100 families) were analyzed. Relatives were included and categorized as affected, unaffected, or unknown. The 35 unaffected family members were used as controls. Five predicted deleterious variants in CCDC141 were identified in 21 individuals (6% of the cohort). Mutations in this gene have been previously described in Kallman syndrome and Isolated Hypogonadotropic Hypogonadism (IHH) [4][5]. CCDC141 is expressed in GnRH migrating neurons and olfactory axons during embryonic development and plays a crucial role in neuronal migration [4][5]. A homology modeling predicted that all variants were deleterious. CCDC141 is known to play a role in the centrosome activity during the migration process [6]. CCDC141 mutants showed abnormal subcellular localization associated with abnormal distribution of acetylated tubulin [6]. Mutant expression led to delayed migration in transfected HEK292.

In conclusion, this study described CCDC141 mutations in SLDP patients for the first time. CCDC141 mutations could lead to abnormal GnRH neuronal migration and lead to a phenotypic spectrum of SLDP or IHH depending on the severity of the defect. This study underlines the importance of embryonic development and cell migration in completing pubertal development.

Reference: 1. Sedlmeyer IL, Palmert MR. (2002) "Delayed puberty: analysis of a large case series from an academic center.," J Clin Endocrinol Metab; 87(4):1613–20. 2. Varimo T, Miettinen PJ, Kansakoski J, Raivio T, Hero M. (2017) "Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center," Hum Reprod; 32(1): 147–153. 3. Wehkalampi K, Widén E, Laine T, Palotie A, Dunkel L. (2008) “Patterns of inheritance of constitutional delay of growth and puberty in families of adolescent girls and boys referred to specialist pediatric care.” J Clin Endocrinol Metab; 93(3):723–8. 4. Turan I, Hutchins BI, Hacihamdioglu B, Kotan LD, Gurbuz F, Ulubay A, Mengen E, Yuksel B, Wray S, Topaloglu AK. (2017) “CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism.” J Clin Endocrinol Metab; 102(6):1816–1825. 5. Hutchins BI, Kotan LD, Taylor-Burds C, Ozkan Y, Cheng PJ, Gurbuz F, Tiong JD, Mengen E, Yuksel B, Topaloglu AK, Wray S. (2016) “CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration“. Endocrinol; 157(5):1956–66. 6. Fukuda T, Sugita S, Inatome R, Yanagi S. (2010) “CAMDI, a novel disrupted in schizophrenia 1 (DISC1)-binding protein, is required for radial migration.” J Biol Chem.; 285(52):40554–61.