RT Journal Article SR Electronic T1 Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 31 OP 37 DO 10.1136/jmedgenet-2019-106011 VO 57 IS 1 A1 Chunyu Liu A1 Mingrong Lv A1 Xiaojin He A1 Yong Zhu A1 Amir Amiri-Yekta A1 Weiyu Li A1 Huan Wu A1 Zine-Eddine Kherraf A1 Wangjie Liu A1 Jingjing Zhang A1 Qing Tan A1 Shuyan Tang A1 Yong-Jun Zhu A1 Yading Zhong A1 Caihua Li A1 Shixiong Tian A1 Zhiguo Zhang A1 Li Jin A1 Pierre Ray A1 Feng Zhang A1 Yunxia Cao YR 2020 UL http://jmg.bmj.com/content/57/1/31.abstract AB 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.