Homozygous mutations in DZIP1 can induce asthenoteratospermia with severe MMAF
Homozygous mutations in DZIP1 can induce asthenoteratospermia with severe MMAF
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DZIP1 纯合突变可诱发伴有严重 MMAF 的弱精子症
DOI：
10.1136/jmedgenet-2019-106479
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发表时间：
2020-07-01
影响因子：
4
通讯作者：
Cao, Yunxia
中科院分区：
文献类型：
--
作者：
Lv, Mingrong;Liu, Wangjie;Cao, Yunxia
弱畸形精子症是男性不育的常见原因之一，常表现为精子头部和/或鞭毛缺陷。精子鞭毛形态异常是弱畸形精子症的常见临床表现之一。DNAH 1、CEP 135、CATSPER 2和SUN 5等基因的变异参与弱畸形精子症的遗传发病。然而，半数以上的弱畸形精子症病例不能用已知的致病基因来解释。方法和结果对两名患有严重MMAF（>90%精子中无鞭毛）的弱畸形精子症患者进行全外显子组测序。第一个先证者具有DZIP 1的纯合错义突变c.188G>A（p.Arg63Gln），第二个先证者具有纯合停止增益突变c.690T>G（p.Tyr230*）。这两种突变在人类基因组数据（1000 Genomes Project，Exome Aggregation Consortium）和我们自己的875名中国汉族对照人群的数据中都没有检测到。DZIP 1编码DAZ（a protein deleted in azospermia）相互作用蛋白，与哺乳动物细胞的中心体相关。中心粒蛋白Centrin 1免疫荧光染色显示先证者精子中心体异常，包括中心粒点不集中或中心粒点多于2个。HEK 293 T细胞转染两个DZIP 1突变的构建体显示降低的DZIP 1水平或截短的DZIP 1。通过CRSIPR-Cas9产生的Dzip 1敲除小鼠显示出严重MMAF的一致表型。结论DZIP 1基因突变可导致弱畸形精子症伴重度MMAF。DZIP 1的缺乏导致精子中心粒功能障碍，并导致鞭毛缺失。
Background Asthenoteratospermia, one of the most common causes for male infertility, often presents with defective sperm heads and/or flagella. Multiple morphological abnormalities of the sperm flagella (MMAF) is one of the common clinical manifestations of asthenoteratospermia. Variants in several genes includingDNAH1,CEP135,CATSPER2andSUN5are involved in the genetic pathogenesis of asthenoteratospermia. However, more than half of the asthenoteratospermia cases cannot be explained by the known pathogenic genes. Methods and results Two asthenoteratospermia-affected men with severe MMAF (absent flagella in >90% spermatozoa) from consanguineous families were subjected to whole-exome sequencing. The first proband had a homozygous missense mutation c.188G>A (p.Arg63Gln) ofDZIP1and the second proband had a homozygous stop-gain mutation c.690T>G (p.Tyr230*). Both of the mutations were neither detected in the human population genome data (1000 Genomes Project, Exome Aggregation Consortium) nor in our own data of a cohort of 875 Han Chinese control populations.DZIP1encodes a DAZ (a protein deleted in azoospermia) interacting protein, which was associated with centrosomes in mammalian cells. Immunofluorescence staining of the centriolar protein Centrin1 indicated that the spermatozoa of the proband presented with abnormal centrosomes, including no concentrated centriolar dot or more than two centriolar dots. HEK293T cells transfected with twoDZIP1-mutated constructs showed reduced DZIP1 level or truncated DZIP1. TheDzip1-knockout mice, generated by the CRSIPR-Cas9, revealed consistent phenotypes of severe MMAF. Conclusion Our study strongly suggests that homozygousDZIP1mutations can induce asthenoteratospermia with severe MMAF. The deficiency of DZIP1 induces sperm centrioles dysfunction and causes the absence of flagella.