Universität zu Köln

Liu, Wensheng ORCID: 0000-0001-7527-5920, Wei, Xiaoli, Liu, Xiaoyan, Chen, Gaowen, Zhang, Xiaoya, Liang, Xiaomei, Isachenko, Vladimir, Sha, Yanwei ORCID: 0000-0002-0321-4915 and Wang, Yifeng . Biallelic mutations in ARMC12 cause asthenozoospermia and multiple midpiece defects in humans and mice. J. Med. Genet.. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

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Abstract

Background Asthenozoospermia is a major factor contributing to male infertility. The mitochondrial sheath (MS), an important organelle in the midpiece of spermatozoa, is crucial to sperm motility. ARMC12 is a mitochondrial peripheral membrane protein. Deletion of Armc12 impairs the arrangement of MS and causes infertility in mice. However, the role of ARMC12 in human asthenozoospermia remains unknown. Objective To study the genetic defects in patients with asthenozoospermia. Methods A total of 125 patients with asthenozoospermia and 120 men with proven fertility were recruited. Whole-exome sequencing and Sanger sequencing were performed for genetic analysis. Papanicolaou staining, HE staining, immunofluorescent staining, transmission electron microscopy and field emission scanning electron microscopy were employed to observe the morphological and structural defects of the spermatozoa and testes. Armc12-knockout mice were generated using the CRISPR-Cas9 system. Intracytoplasmic sperm injection was used to treat the patients. Results Biallelic ARMC12 mutations were identified in three patients, including homozygous mutations in two siblings from a consanguineous family and compound heterozygous mutations in one sporadic patient. ARMC12 is mainly expressed in the midpiece of elongated and late spermatids in the human testis. The patients' spermatozoa displayed multiple midpiece defects, including absent MS and central pair, scattered or forked axoneme and incomplete plasma membrane. Spermatozoa from Armc12(-/-) mice showed parallel defects in the midpiece. Moreover, two patients were treated with intracytoplasmic sperm injection and achieved good outcomes. Conclusion Our findings prove for the first time that defects in ARMC12 cause asthenozoospermia and multiple midpiece defects in humans.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Liu, Wensheng UNSPECIFIED orcid.org/0000-0001-7527-5920 UNSPECIFIED Wei, Xiaoli UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Xiaoyan UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, Gaowen UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Xiaoya UNSPECIFIED UNSPECIFIED UNSPECIFIED Liang, Xiaomei UNSPECIFIED UNSPECIFIED UNSPECIFIED Isachenko, Vladimir UNSPECIFIED UNSPECIFIED UNSPECIFIED Sha, Yanwei UNSPECIFIED orcid.org/0000-0002-0321-4915 UNSPECIFIED Wang, Yifeng UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-682681
DOI:	10.1136/jmedgenet-2021-108137
Journal or Publication Title:	J. Med. Genet.
Publisher:	BMJ PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1468-6244
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTRACYTOPLASMIC SPERM INJECTION; ARMADILLO REPEAT; MITOCHONDRIAL SHEATH; TAIL; PROTEIN; ASSOCIATION; SPERMATOZOA; INFERTILITY; GENE Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68268