Universität zu Köln

Sudhakar, Digumarthi V. S., Phanindranath, Regur, Jaishankar, Shveta, Ramani, Anand, Kalamkar, Kaustubh P., Kumar, Umesh, Pawar, Asmita D., Dada, Rima, Singh, Rajender, Gupta, Nalini J., Deenadayal, Mamata, Tolani, Aarti Deenadayal, Sharma, Yogendra, Anand, Anuranjan, Gopalakrishnan, Jay ORCID: 0000-0001-5907-3982 and Thangaraj, Kumarasamy . Exome sequencing and functional analyses revealed CETN1 variants leads to impaired cell division and male fertility. Hum. Mol. Genet.. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Human spermatogenesis requires an orchestrated expression of numerous genes in various germ cell subtypes. Therefore, the genetic landscape of male infertility is highly complex. Known genetic factors alone account for at least 15% of male infertility. However, similar to 40% of infertile men remain undiagnosed and are classified as idiopathic infertile men. We performed exome sequencing in 47 idiopathic infertile men (discovery cohort), followed by replication study (40 variants in 33 genes) in 844 infertile men and 709 controls using Sequenom MassARRAY((R)) based genotyping. We report 17 variants in twelve genes that comprise both previously reported (DNAH8, DNAH17, FISP2 and SPEF2) and novel candidate genes (BRDT, CETN1, CATSPERD, GMCL1, SPATA6, TSSK4, TSKS and ZNF318) for male infertility. The latter have a strong biological nexus to human spermatogenesis and their respective mouse knockouts are concordant with human phenotypes. One candidate gene CETN1, identified in this study, was sequenced in another independent cohort of 840 infertile and 689 fertile men. Further, CETN1 variants were functionally characterized using biophysical and cell biology approaches. We demonstrate that CETN1 variant- p.Met72Thr leads to multipolar cells, fragmented nuclei during mitosis leading to cell death and show significantly perturbed ciliary disassembly dynamics. Whereas CETN1-5 ' UTR variant; rs367716858 leads to loss of a methylation site and increased reporter gene expression in vitro. We report a total of eight novel candidate genes identified by exome sequencing, which may have diagnostic relevance and can contribute to improved diagnostic workup and clinical management of male infertility.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sudhakar, Digumarthi V. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Phanindranath, Regur UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaishankar, Shveta UNSPECIFIED UNSPECIFIED UNSPECIFIED Ramani, Anand UNSPECIFIED UNSPECIFIED UNSPECIFIED Kalamkar, Kaustubh P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kumar, Umesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Pawar, Asmita D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dada, Rima UNSPECIFIED UNSPECIFIED UNSPECIFIED Singh, Rajender UNSPECIFIED UNSPECIFIED UNSPECIFIED Gupta, Nalini J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Deenadayal, Mamata UNSPECIFIED UNSPECIFIED UNSPECIFIED Tolani, Aarti Deenadayal UNSPECIFIED UNSPECIFIED UNSPECIFIED Sharma, Yogendra UNSPECIFIED UNSPECIFIED UNSPECIFIED Anand, Anuranjan UNSPECIFIED UNSPECIFIED UNSPECIFIED Gopalakrishnan, Jay UNSPECIFIED orcid.org/0000-0001-5907-3982 UNSPECIFIED Thangaraj, Kumarasamy UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-692861
DOI:	10.1093/hmg/ddac216
Journal or Publication Title:	Hum. Mol. Genet.
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MALE-INFERTILITY; PRIMARY CILIUM; SPERMATOGENESIS; ABNORMALITIES; GENE Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69286