Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility

J Med Genet. 2020 Jan;57(1):31-37. doi: 10.1136/jmedgenet-2019-106011.

Chunyu Liu ^# ¹ ² ³ ⁴, Mingrong Lv ^# ⁴ ⁵ ⁶, Xiaojin He ^# ⁴ ⁵ ⁶, Yong Zhu ^# ¹, Amir Amiri-Yekta ⁷ ⁸ ⁹, Weiyu Li ¹ ² ³, Huan Wu ⁴ ⁵ ⁶, Zine-Eddine Kherraf ⁷ ⁸, Wangjie Liu ¹ ² ³, Jingjing Zhang ⁴ ⁵ ⁶, Qing Tan ⁴ ⁵ ⁶, Shuyan Tang ¹ ² ³, Yong-Jun Zhu ¹⁰, Yading Zhong ¹¹, Caihua Li ¹², Shixiong Tian ¹, Zhiguo Zhang ⁴ ⁵ ⁶, Li Jin ¹, Pierre Ray ^# ⁷ ⁸, Feng Zhang ¹³ ² ³ ⁴, Yunxia Cao ¹⁴ ⁵ ⁶

Affiliations

1 Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), 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 State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
4 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
5 Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China.
6 Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China.
7 Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
8 Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble, France.
9 Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture, and Research, Tehran, Iran.
10 Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China.
11 Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
12 Genesky Biotechnologies Inc, Shanghai, China.
13 Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China [email protected] [email protected].
14 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China [email protected] [email protected].
# Contributed equally.

PMID: 31048344 DOI: 10.1136/jmedgenet-2019-106011

Abstract

Background: Male infertility due to multiple morphological abnormalities of the sperm flagella (MMAF) is a genetically heterogeneous disorder. Previous studies revealed several MMAF-associated genes, which account for approximately 60% of human MMAF cases. The pathogenic mechanisms of MMAF remain to be illuminated.

Methods and results: We conducted genetic analyses using whole-exome sequencing in 50 Han Chinese probands with MMAF. Two homozygous stop-gain variants (c.910C>T (p.Arg304*) and c.3400delA (p.Ile1134Serfs*13)) of the SPEF2 (sperm flagellar 2) gene were identified in two unrelated consanguineous families. Consistently, an Iranian subject from another cohort also carried a homozygous SPEF2 stop-gain variant (c.3240delT (p.Phe1080Leufs*2)). All these variants affected the long SPEF2 transcripts that are expressed in the testis and encode the IFT20 (intraflagellar transport 20) binding domain, important for sperm tail development. Notably, previous animal studies reported spontaneous mutations of SPEF2 causing sperm tail defects in bulls and pigs. Our further functional studies using immunofluorescence assays showed the absence or a remarkably reduced staining of SPEF2 and of the MMAF-associated CFAP69 protein in the spermatozoa from SPEF2-affected subjects.

Conclusions: We identified SPEF2 as a novel gene for human MMAF across the populations. Functional analyses suggested that the deficiency of SPEF2 in the mutated subjects could alter the localisation of other axonemal proteins.

Keywords

exome; infertility; sequencing; spef2; sperm.

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