Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA

Shixiong Tian; Chaofeng Tu; Xiaojin He; Lanlan Meng; Jiaxiong Wang; Shuyan Tang; Yang Gao; Chunyu Liu; Huan Wu; Yiling Zhou; Mingrong Lv; Ge Lin; Li Jin; Yunxia Cao; Dongdong Tang; Feng Zhang; Yue-Qiu Tan

doi:10.1136/jmg-2022-108887

Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA

J Med Genet. 2023 Aug;60(8):827-834. doi: 10.1136/jmg-2022-108887. Epub 2023 Jan 2.

Authors

Shixiong Tian^{1

2}, Chaofeng Tu^{3

4}, Xiaojin He^{5

6

7}, Lanlan Meng^{3

4}, Jiaxiong Wang⁸, Shuyan Tang¹, Yang Gao^{5

6}, Chunyu Liu¹, Huan Wu^{5

6

7}, Yiling Zhou¹, Mingrong Lv^{5

6

7}, Ge Lin^{3

4}, Li Jin¹, Yunxia Cao^{5

6

7}, Dongdong Tang^{9

6

7}, Feng Zhang^{10

2}, Yue-Qiu Tan^{11

4}

Affiliations

¹ Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
² Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China.
³ Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China.
⁴ Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.
⁵ Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁶ NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China.
⁷ Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei, China.
⁸ Center for Reproduction and Genetics, State Key Laboratory of Reproductive Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China.
⁹ Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China [email protected] [email protected] [email protected].
¹⁰ Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China [email protected] [email protected] [email protected].
¹¹ Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China [email protected] [email protected] [email protected].

PMID: 36593121
DOI: 10.1136/jmg-2022-108887

Abstract

Background: Spermatogenic impairments can lead to male infertility by different pathological conditions, such as multiple morphological abnormalities of the sperm flagella (MMAF) and non-obstructive azoospermia (NOA). Genetic factors are involved in impaired spermatogenesis.

Methods and results: Here, we performed genetic analyses through whole-exome sequencing in a cohort of 334 Han Chinese probands with severe MMAF or NOA. Biallelic variants of CFAP54 were identified in three unrelated men, including one homozygous frameshift variant (c.3317del, p.Phe1106Serfs*19) and two compound heterozygous variants (c.878G>A, p.Arg293His; c.955C>T, p.Arg319Cys and c.4885C>T, p.Arg1629Cys; c.937G>A, p.Gly313Arg). All of the identified variants were absent or extremely rare in the public human genome databases and predicted to be damaging by bioinformatic tools. The men harbouring CFAP54 mutations exhibited abnormal sperm morphology, reduced sperm concentration and motility in ejaculated semen. Significant axoneme disorganisation and other ultrastructure abnormities were also detected inside the sperm cells from men harbouring CFAP54 mutations. Furthermore, immunofluorescence assays showed remarkably reduced staining of four flagellar assembly-associated proteins (IFT20, IFT52, IFT122 and SPEF2) in the spermatozoa of CFAP54-deficient men. Notably, favourable clinical pregnancy outcomes were achieved with sperm from men carrying CFAP54 mutations after intracytoplasmic sperm injection treatment.

Conclusion: Our genetic analyses and experimental observations revealed that biallelic deleterious mutations of CFAP54 can induce severe MMAF and NOA in humans.

Keywords: Genetics, Medical.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Azoospermia* / pathology
Cytoskeletal Proteins* / genetics
Female
Humans
Infertility, Male* / pathology
Male
Mutation
Pregnancy
Sperm Tail / pathology
Spermatozoa / pathology

Substances

Cytoskeletal Proteins

Supplementary concepts

Azoospermia, Nonobstructive