RT Journal Article
SR Electronic
T1 Homozygous mutations in <em>CCDC34</em> cause male infertility with oligoasthenoteratozoospermia in humans and mice
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 710
OP 718
DO 10.1136/jmedgenet-2021-107919
VO 59
IS 7
A1 Jiangshan Cong
A1 Xiong Wang
A1 Amir Amiri-Yekta
A1 Lingbo Wang
A1 Zine-Eddine Kherraf
A1 Chunyu Liu
A1 Caroline Cazin
A1 Shuyan Tang
A1 Seyedeh Hanieh Hosseini
A1 Shixiong Tian
A1 Abbas Daneshipour
A1 Jiaxiong Wang
A1 Yiling Zhou
A1 Yuyan Zeng
A1 Shenmin Yang
A1 Xiaojin He
A1 Jinsong Li
A1 Yunxia Cao
A1 Li Jin
A1 Pierre F Ray
A1 Feng Zhang
YR 2022
UL http://jmg.bmj.com/content/59/7/710.abstract
AB Background Oligoasthenoteratozoospermia is a typical feature of sperm malformations leading to male infertility. Only a few genes have been clearly identified as pathogenic genes of oligoasthenoteratozoospermia.Methods and results Here, we identified a homozygous frameshift variant (c.731dup, p.Asn244Lysfs*3) in CCDC34, which is preferentially expressed in the human testis, using whole-exome sequencing in a cohort of 100 Chinese men with multiple morphological abnormalities of the sperm flagella (MMAF). In an additional cohort of 167 MMAF-affected men from North Africa, Iran and France, we identified a second subject harbouring a homozygous CCDC34 frameshift variant (c.799_817del, p.Glu267Lysfs*72). Both affected men presented a typical MMAF phenotype with an abnormally low sperm concentration (ie, oligoasthenoteratozoospermia). Transmission electron microscopy analysis of the sperm flagella affected by CCDC34 deficiency further revealed dramatic disorganisation of the axoneme. Immunofluorescence assays of the spermatozoa showed that CCDC34 deficiency resulted in almost absent staining of CCDC34 and intraflagellar transport-B complex-associated proteins (such as IFT20 and IFT52). Furthermore, we generated a mouse Ccdc34 frameshift mutant using CRISPR-Cas9 technology. Ccdc34-mutated (Ccdc34mut/mut ) male mice were sterile and presented oligoasthenoteratozoospermia with typical MMAF anomalies. Intracytoplasmic sperm injection has good pregnancy outcomes in both humans and mice.Conclusions Our findings support that CCDC34 is crucial to the formation of sperm flagella and that biallelic deleterious mutations in CCDC34/Ccdc34 cause male infertility with oligoasthenoteratozoospermia in humans and mice.All data relevant to the study are included in the article or uploaded as supplementary information.