Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility
Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility
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SPEF2纯合突变诱导精子鞭毛多种形态异常和男性不育
DOI：
10.1136/jmedgenet-2019-106011
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Cao, Yunxia
中科院分区：
文献类型：
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作者：
Liu, Chunyu;Lv, Mingrong;Cao, Yunxia
背景：精子鞭毛多形态异常（MMAF）导致的男性不育是一种遗传异质性疾病。先前的研究揭示了几种MMAF相关基因，约占人类MMAF病例的60%。MMAF的致病机制仍有待阐明。方法和结果我们使用全外显子组测序技术对50名汉族MMAF先证者进行了遗传分析。在两个无血缘关系的家系中发现了SPEF2基因的两个纯合停止增益变体（c.910C>T（p.Arg304*）和c.3400delA（p.Ile1134Serfs*13））。同样，来自另一队列的1例伊朗受试者也携带纯合子SPEF2停止增益变体（c.3240delT（p.Phe1080Leufs*2））。所有这些变体都影响了在睾丸中表达的SPEF2长转录本，并编码对精子尾部发育重要的IFT 20（鞭毛内转运20）结合结构域。值得注意的是，以前的动物研究报告了SPEF2的自发突变导致公牛和猪的精子尾部缺陷。我们进一步的功能研究，使用免疫荧光分析显示，SPEF2和MMAF相关的CFAP 69蛋白在SPEF2受影响的受试者的精子中的染色的情况下或显着减少。结论SPEF2是一个新的人类MMAF基因。功能分析表明，突变受试者中SPEF2的缺乏可能会改变其他轴丝蛋白的定位。
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.