TY - JOUR T1 - Homozygous mutations in <em>SPEF2</em> induce multiple morphological abnormalities of the sperm flagella and male infertility JF - Journal of Medical Genetics JO - J Med Genet SP - 31 LP - 37 DO - 10.1136/jmedgenet-2019-106011 VL - 57 IS - 1 AU - Chunyu Liu AU - Mingrong Lv AU - Xiaojin He AU - Yong Zhu AU - Amir Amiri-Yekta AU - Weiyu Li AU - Huan Wu AU - Zine-Eddine Kherraf AU - Wangjie Liu AU - Jingjing Zhang AU - Qing Tan AU - Shuyan Tang AU - Yong-Jun Zhu AU - Yading Zhong AU - Caihua Li AU - Shixiong Tian AU - Zhiguo Zhang AU - Li Jin AU - Pierre Ray AU - Feng Zhang AU - Yunxia Cao Y1 - 2020/01/01 UR - http://jmg.bmj.com/content/57/1/31.abstract N2 - 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&gt;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. ER -