Homozygous mutations in CCDC34 cause male infertility with oligoasthenoteratozoospermia in humans and mice

J Med Genet. 2022 Jul;59(7):710-718. doi: 10.1136/jmedgenet-2021-107919.

Jiangshan Cong ^# ¹ ², Xiong Wang ^# ³ ⁴, Amir Amiri-Yekta ^# ⁵ ⁶, Lingbo Wang ^# ¹ ², Zine-Eddine Kherraf ⁶ ⁷, Chunyu Liu ¹ ², Caroline Cazin ⁶ ⁷ ⁸, Shuyan Tang ¹ ², Seyedeh Hanieh Hosseini ⁹, Shixiong Tian ¹ ², Abbas Daneshipour ⁵, Jiaxiong Wang ¹⁰ ¹¹, Yiling Zhou ¹ ², Yuyan Zeng ¹, Shenmin Yang ¹⁰ ¹¹, Xiaojin He ¹² ¹³ ¹⁴, Jinsong Li ¹⁵ ¹⁶, Yunxia Cao ¹² ¹³ ¹⁴, Li Jin ¹, Pierre F Ray ¹⁷ ⁷, Feng Zhang ¹⁸ ²

Affiliations

1 Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China.
2 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
3 Department of Surgery, Medical College of Shandong University, Jinan, Shandong, China.
4 Reproductive Medicine Center, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China.
5 Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture, and Research, Tehran, Iran.
6 Université Grenoble Alpes, Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Grenoble, France.
7 Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble, France.
8 Laboratoire Eurofins Biomnis, Lyon, France.
9 Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture, and Research, Tehran, Iran.
10 State Key Laboratory of Reproductive Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.
11 Suzhou Municipal Hospital, Suzhou, Jiangsu, China.
12 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
13 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China.
14 MOE Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, Anhui, China.
15 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
16 University of the Chinese Academy of Sciences, Shangai, China.
17 Université Grenoble Alpes, Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Grenoble, France [email protected] [email protected].
18 Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China [email protected] [email protected].
# Contributed equally.

PMID: 34348960 DOI: 10.1136/jmedgenet-2021-107919

Abstract

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 (Ccdc34^mut/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.

Keywords

genetic variation; genetics; medical; reproductive medicine.

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