Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China.
J Med Genet. 2020 Jul;57(7):445-453. doi: 10.1136/jmedgenet-2019-106479. Epub 2020 Feb 12.
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 including , , and are involved in the genetic pathogenesis of asthenoteratospermia. However, more than half of the asthenoteratospermia cases cannot be explained by the known pathogenic genes.
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) of and 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. encodes 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 two -mutated constructs showed reduced DZIP1 level or truncated DZIP1. The -knockout mice, generated by the CRSIPR-Cas9, revealed consistent phenotypes of severe MMAF.
Our study strongly suggests that homozygous mutations can induce asthenoteratospermia with severe MMAF. The deficiency of DZIP1 induces sperm centrioles dysfunction and causes the absence of flagella.
弱精子症是男性不育症的最常见原因之一，常表现为精子头部和/或鞭毛缺陷。精子鞭毛多发形态异常（MMAF）是弱精子症的常见临床表现之一。几个基因的变异，包括 、 、 和 ，参与了弱精子症的遗传发病机制。然而，超过一半的弱精子症病例无法用已知的致病基因来解释。
两个来自近亲家庭的患有严重 MMAF（>90%精子无鞭毛）的弱精子症患者接受了全外显子组测序。第一个先证者携带一个纯合错义突变 c.188G>A（p.Arg63Gln），第二个先证者携带一个纯合终止突变 c.690T>G（p.Tyr230*）。这两种突变均未在人类基因组数据（1000 基因组计划、外显子聚合联盟）或我们自己的 875 名汉族对照人群数据中检测到。 编码一个 DAZ（无精子症缺失蛋白）相互作用蛋白，该蛋白与哺乳动物细胞中的中心体有关。中心体蛋白 Centrin1 的免疫荧光染色表明，先证者的精子存在异常中心体，包括没有浓缩的中心粒点或超过两个中心粒点。转染了两个 -突变构建体的 HEK293T 细胞显示 DZIP1 水平降低或 DZIP1 截断。通过 CRSIPR-Cas9 产生的 -敲除小鼠表现出严重 MMAF 的一致表型。
我们的研究强烈表明，纯合 突变可导致严重 MMAF 的弱精子症。DZIP1 的缺乏导致精子中心体功能障碍，并导致鞭毛缺失。
