Homozygous missense mutation L673P in adenylate kinase 7 (AK7) leads to primary male infertility and multiple morphological anomalies of the flagella but not to primary ciliary dyskinesia
Homozygous missense mutation L673P in adenylate kinase 7 (AK7) leads to primary male infertility and multiple morphological anomalies of the flagella but not to primary ciliary dyskinesia
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DOI：
10.1093/hmg/ddy034
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发表时间：
2018-04-01
影响因子：
3.5
通讯作者：
Toure, Aminata
中科院分区：
文献类型：
--
作者：
Lores, Patrick;Coutton, Charles;Toure, Aminata
运动纤毛和精子鞭毛共享一个非常保守的微管为基础的细胞骨架，称为轴丝，它维持两个细胞器的跳动和运动。众所周知，这种轴丝的超微结构和/或功能缺陷会引起原发性纤毛运动障碍（PCD），这是一种以反复呼吸道感染、慢性中耳炎、逆位、男性不育和最严重的脑积水为特征的疾病。直到最近，编码轴丝蛋白的基因突变在睾丸中优先表达被确定在孤立的男性不育症，在这些情况下，个人表现出严重的弱精子症由于精子鞭毛（MMAF），但没有PCD功能的多形态学Abligence。在这项研究中，我们对两个没有任何呼吸PCD特征的MMAF兄弟姐妹进行了遗传调查，我们报告了AK 7中c.2018T>G（p.Leu673Pro）颠换的鉴定，AK 7编码腺苷酸激酶，在纤毛组织和睾丸中表达。通过对来自携带颠换的个体的生物样品进行转录和蛋白质分析，我们证明这种突变导致精子细胞中AK 7蛋白的丢失，而不是呼吸纤毛细胞中AK 7蛋白的丢失，尽管两种细胞类型都携带突变的转录本并且没有检测到组织特异性亚型。因此，这项工作支持这样的观点，即纤毛和精子鞭毛共享的蛋白质可能在每个细胞器中具有特定的性质和/或功能，这与它们的组装和组织模式的差异一致。总的来说，这项工作确定了MMAF导致弱精子症的一种新的遗传原因，并表明在人类中，AK 7的更有害突变可能会诱导PCD。
Motile cilia and sperm flagella share an extremely conserved microtubule-based cytoskeleton, called the axoneme, which sustains beating and motility of both organelles. Ultra-structural and/or functional defects of this axoneme are well-known to cause primary ciliary dyskinesia (PCD), a disorder characterized by recurrent respiratory tract infections, chronic otitis media, situs inversus, male infertility and in most severe cases, hydrocephalus. Only recently, mutations in genes encoding axonemal proteins with preferential expression in the testis were identified in isolated male infertility; in those cases, individuals displayed severe asthenozoospermia due to Multiple Morphological Abnormalities of the sperm Flagella (MMAF) but not PCD features. In this study, we performed genetic investigation of two siblings presenting MMAF without any respiratory PCD features, and we report the identification of the c.2018T>G (p.Leu673Pro) transversion in AK7, encoding an adenylate kinase, expressed in ciliated tissues and testis. By performing transcript and protein analyses of biological samples from individual carrying the transversion, we demonstrate that this mutation leads to the loss of AK7 protein in sperm cells but not in respiratory ciliated cells, although both cell types carry the mutated transcript and no tissue-specific isoforms were detected. This work therefore, supports the notion that proteins shared by both cilia and sperm flagella may have specific properties and/or function in each organelle, in line with the differences in their mode of assembly and organization. Overall, this work identifies a novel genetic cause of asthenozoospermia due to MMAF and suggests that in humans, more deleterious mutations of AK7 might induce PCD.