Teratozoospermia: spotlight on the main genetic actors in the human
Teratozoospermia: spotlight on the main genetic actors in the human
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DOI：
10.1093/humupd/dmv020
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发表时间：
2015-07-01
影响因子：
13.3
通讯作者：
Ray, Pierre F.
中科院分区：
文献类型：
--
作者：
Coutton, Charles;Escoffier, Jessica;Ray, Pierre F.
男性不育症影响全世界超过2000万男性，是一个主要的健康问题。虽然多因素，男性不育症有一个强大的遗传基础，迄今尚未得到广泛的研究。然而，最近对近亲家庭和表型同质性患者的小队列的研究已经允许确定一些常染色体隐性遗传畸形精子症的原因。极光激酶C（AURKC）的纯合突变首先被描述为是大多数巨精子症病例的原因。后来在球形精子症患者的精子发生相关16（SPATA 16）和dpy-19样2（DPY 19 L2）中发现了其他基因缺陷，最近在一组表现为鞭毛异常的异质性患者中发现了动力蛋白、轴丝、重链1（DNA H1）缺陷，这些患者先前被描述为纤维鞘发育不良或短尾/残尾综合征，本文对PubMed/Medline中有关畸形精子症（特别是球形精子症、大头精子和鞭毛异常）的人类遗传学、实验模型和生理病理学研究文献进行了全面综述。检索包括2014年9月之前在线提供英文摘要的所有文章。对大量不相关的球形精子症和大头精子患者的分子研究证实，DPY 19 L2和AURKC突变是其各自病理表型的主要原因。在球形精子症中，DPY 19 L2基因的全部缺失代表类似于81%的病理等位基因，但也描述了影响蛋白质功能的点突变。在巨精子症中，AURKC中仅发现两个复发突变，占几乎所有的病理等位基因，提高了杂合子个体的假定阳性选择的可能性。最近在一定比例的MMAF患者中鉴定出DNAH 1突变是有希望的，但强调这种表型是遗传异质性的。此外，动力蛋白突变的鉴定加强了新出现的观点，即MMAF可能是原发性纤毛运动障碍的经典形式的表型变异。基于人类和动物模型的数据，MMAF表型似乎是有利的缺陷直接或间接影响中央对轴丝微管的精子flagella.The研究提供了有价值的信息，遗传和分子缺陷导致不育，以提高我们的理解畸形精子症的生理病理学，同时给出了一个详细的特征精子发生。此外，这些发现对畸形精子症患者的诊断策略具有重要影响，允许临床医生为患者提供知情的遗传咨询，采用最佳治疗过程，并开发直接针对缺陷基因产物的个性化药物。
Male infertility affects > 20 million men worldwide and represents a major health concern. Although multifactorial, male infertility has a strong genetic basis which has so far not been extensively studied. Recent studies of consanguineous families and of small cohorts of phenotypically homogeneous patients have however allowed the identification of a number of autosomal recessive causes of teratozoospermia. Homozygous mutations of aurora kinase C (AURKC) were first described to be responsible for most cases of macrozoospermia. Other genes defects have later been identified in spermatogenesis associated 16 (SPATA16) and dpy-19-like 2 (DPY19L2) in patients with globozoospermia and more recently in dynein, axonemal, heavy chain 1 (DNAH1) in a heterogeneous group of patients presenting with flagellar abnormalities previously described as dysplasia of the fibrous sheath or short/stump tail syndromes, which we propose to call multiple morphological abnormalities of the flagella (MMAF).A comprehensive review of the scientific literature available in PubMed/Medline was conducted for studies on human genetics, experimental models and physiopathology related to teratozoospermia in particular globozoospermia, large headed spermatozoa and flagellar abnormalities. The search included all articles with an English abstract available online before September 2014.Molecular studies of numerous unrelated patients with globozoospermia and large-headed spermatozoa confirmed that mutations in DPY19L2 and AURKC are mainly responsible for their respective pathological phenotype. In globozoospermia, the deletion of the totality of the DPY19L2 gene represents similar to 81% of the pathological alleles but point mutations affecting the protein function have also been described. In macrozoospermia only two recurrent mutations were identified in AURKC, accounting for almost all the pathological alleles, raising the possibility of a putative positive selection of heterozygous individuals. The recent identification of DNAH1 mutations in a proportion of patients with MMAF is promising but emphasizes that this phenotype is genetically heterogeneous. Moreover, the identification of mutations in a dynein strengthens the emerging point of view that MMAF may be a phenotypic variation of the classical forms of primary ciliary dyskinesia. Based on data from human and animal models, the MMAF phenotype seems to be favored by defects directly or indirectly affecting the central pair of axonemal microtubules of the sperm flagella.The studies described here provide valuable information regarding the genetic and molecular defects causing infertility, to improve our understanding of the physiopathology of teratozoospermia while giving a detailed characterization of specific features of spermatogenesis. Furthermore, these findings have a significant influence on the diagnostic strategy for teratozoospermic patients allowing the clinician to provide the patient with informed genetic counseling, to adopt the best course of treatment and to develop personalized medicine directly targeting the defective gene products.