PT  - JOURNAL ARTICLE
AU  - Jiangshan Cong
AU  - Xiong Wang
AU  - Amir Amiri-Yekta
AU  - Lingbo Wang
AU  - Zine-Eddine Kherraf
AU  - Chunyu Liu
AU  - Caroline Cazin
AU  - Shuyan Tang
AU  - Seyedeh Hanieh Hosseini
AU  - Shixiong Tian
AU  - Abbas Daneshipour
AU  - Jiaxiong Wang
AU  - Yiling Zhou
AU  - Yuyan Zeng
AU  - Shenmin Yang
AU  - Xiaojin He
AU  - Jinsong Li
AU  - Yunxia Cao
AU  - Li Jin
AU  - Pierre F Ray
AU  - Feng Zhang
TI  - Homozygous mutations in <em>CCDC34</em> cause male infertility with oligoasthenoteratozoospermia in humans and mice
AID  - 10.1136/jmedgenet-2021-107919
DP  - 2022 Jul 01
TA  - Journal of Medical Genetics
PG  - 710--718
VI  - 59
IP  - 7
4099  - http://jmg.bmj.com/content/59/7/710.short
4100  - http://jmg.bmj.com/content/59/7/710.full
SO  - J Med Genet2022 Jul 01; 59
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.