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

被引:67
作者
Liu, Chunyu [1 ,2 ,3 ,4 ]
Lv, Mingrong [4 ,5 ,6 ]
He, Xiaojin [4 ,5 ,6 ]
Zhu, Yong [1 ]
Amiri-Yekta, Amir [7 ,8 ,9 ]
Li, Weiyu [1 ,2 ,3 ]
Wu, Huan [4 ,5 ,6 ]
Kherraf, Zine-Eddine [7 ,8 ]
Liu, Wangjie [1 ,2 ,3 ]
Zhang, Jingjing [4 ,5 ,6 ]
Tan, Qing [4 ,5 ,6 ]
Tang, Shuyan [1 ,2 ,3 ]
Zhu, Yong-Jun [10 ]
Zhong, Yading [11 ]
Li, Caihua [12 ]
Tian, Shixiong [1 ]
Zhang, Zhiguo [4 ,5 ,6 ]
Jin, Li [1 ]
Ray, Pierre [7 ,8 ]
Zhang, Feng [1 ,2 ,3 ,4 ]
Cao, Yunxia [4 ,5 ,6 ]
机构
[1] Fudan Univ, Sch Life Sci, Obstet & Gynecol Hosp,State Key Lab Genet Engn, NHC Key Lab Reprod Regulat,Shanghai Inst Planned, Shanghai, Peoples R China
[2] Shanghai Key Lab Female Reprod Endocrine Related, Shanghai, Peoples R China
[3] Nanjing Med Univ, Ctr Global Hlth, Sch Publ Hlth, State Key Lab Reprod Med, Nanjing, Jiangsu, Peoples R China
[4] Anhui Med Univ, Reprod Med Ctr, Dept Obstet & Gynecol, Affiliated Hosp 1, Hefei, Anhui, Peoples R China
[5] Anhui Med Univ, Anhui Prov Key Lab Reprod Hlth & Genet, Hefei, Anhui, Peoples R China
[6] Anhui Prov Engn Technol Res Ctr Biopreservat & Ar, Hefei, Anhui, Peoples R China
[7] Univ Grenoble Alpes, Genet Epigenet & Therapies Infertil, Inst Adv Biosci, INSERM U1209,CNRS UMR 5309, Grenoble, France
[8] CHU Grenoble, UM GI DPI, Grenoble, France
[9] Acad Ctr Educ Culture & Res, Dept Genet, Reprod Biomed Res Ctr, Royan Inst Reprod Biomed, Tehran, Iran
[10] Fudan Univ, Huashan Hosp, Dept Thorac Surg, Shanghai, Peoples R China
[11] Anhui Med Univ, Dept Radiol, Affiliated Hosp 1, Hefei, Anhui, Peoples R China
[12] Genesky Biotechnol Inc, Shanghai, Peoples R China
基金
中国国家自然科学基金;
关键词
spef2; sperm; infertility; exome; sequencing; SPERMATOGENESIS; TRANSPORT;
D O I
10.1136/jmedgenet-2019-106011
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:31 / 37
页数:7
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