The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population
The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population
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DOI：
10.1093/hmg/ddp029
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发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Ray, Pierre F.
中科院分区：
文献类型：
--
作者：
Dieterich, Klaus;Zouari, Raoudha;Ray, Pierre F.
全世界至少有7 000万对夫妇患有不孕症。很大一部分病例被认为具有遗传成分，但迄今为止几乎没有发现致病基因。在先前的研究中，我们证明了极光激酶C（AURKC）基因中的纯合突变（c.144delC）导致产生大头多倍体多鞭毛精子，这是主要在北非人中观察到的原发性不育表型。我们现在想估计缺陷的患病率，以提高我们对AURKC在精子发生中的生理病理学的理解，并评估其在卵子发生中的意义。从马格里布一般人群的个体中确定的携带者频率为1/50，与Y-微缺失相当，Y-微缺失是迄今为止唯一已知的改变精子发生的复发性遗传事件。共有62例患者进行了基因分型，所有具有接近100%大头精子的典型表型的患者均发生同源突变（n = 32），而在其他患者中未检测到AURKC突变。两个纯合子女性被确定;都是可育的，表明AURKC是不是卵子发生中必不可少的。先前的FISH结果显示这些患者的精子具有很大的染色体异质性。我们在这里通过流式细胞术证明，所有的精子实际上都具有均一的4C DNA含量，因此在第一次减数分裂前都被阻断。因此，我们的数据表明，一个功能性的AURKC蛋白是必要的男性减数分裂胞质分裂，而它的缺乏不会损害卵子发生。
Infertility concerns a minimum of 70 million couples worldwide. An important proportion of cases is believed to have a genetic component, yet few causal genes have been identified so far. In a previous study, we demonstrated that a homozygous mutation (c.144delC) in the Aurora Kinase C (AURKC) gene led to the production of large-headed polyploid multi-flagellar spermatozoa, a primary infertility phenotype mainly observed in North Africans. We now want to estimate the prevalence of the defect, to improve our understanding of AURKC physiopathology in spermatogenesis and assess its implication in oogenesis. A carrier frequency of 1/50 was established from individuals from the Maghrebian general population, comparable to that of Y-microdeletions, thus far the only known recurrent genetic event altering spermatogenesis. A total of 62 patients were genotyped, all who had a typical phenotype with close to 100% large-headed spermatozoa were homozygously mutated (n = 32), whereas no AURKC mutations were detected in the others. Two homozygous females were identified; both were fertile indicating that AURKC is not indispensible in oogenesis. Previous FISH results had showed a great chromosomal heterogeneity in these patient's spermatozoa. We demonstrate here by flow cytometry that all spermatozoa have in fact a homogeneous 4C DNA content and are thus all blocked before the first meiotic division. Our data thus indicate that a functional AURKC protein is necessary for male meiotic cytokinesis while its absence does not impair oogenesis.