Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family
Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family
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DOI：
10.1093/hmg/ddv290
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发表时间：
2015-10-01
影响因子：
3.5
通讯作者：
Viville, Stephane
中科院分区：
文献类型：
--
作者：
Okutman, Ozlem;Muller, Jean;Viville, Stephane
不孕症是一个全球性的医疗保健问题，尽管多年的辅助生殖活动，大量的情况下仍然特发性。我们目前对人类配子发生的基本机制的理解有限，严重限制了不孕症患者临床护理的改善。使用外显子组测序，我们确定了一个无义突变，导致TEX15位点（c.2130T>G，p.Y710*）的过早停止在一个近亲土耳其家庭，包括8个兄弟姐妹，其中3个兄弟被确定为不育。TEX15基因定位于8号染色体，具有睾丸特异性表达，包含4个外显子，编码一个2789个氨基酸的蛋白质，功能尚不确定。该突变，这将导致早期翻译终止在第一外显子的TEX15，共分离与不育表型，我们的数据强烈表明，这是在家庭中的生精缺陷的原因。所有三个受影响的兄弟提出了一个表型，让人想起在KO小鼠中观察到的。事实上，以前报道的结果表明，在小鼠中的orthopathy基因的破坏导致睾丸大小急剧减少和减数分裂阻滞在精子发生的第一波在男性，而女性KO小鼠是可生育的。我们对一个土耳其家庭的研究数据表明，随着时间的推移，所发现的突变与精子数量减少有关。一个诊断性的测试，确定在男人的突变可以提供一个精子发生失败的迹象，并促使患者进行精子冷冻保存在早期的年龄。
Infertility is a global healthcare problem, and despite long years of assisted reproductive activities, a significant number of cases remain idiopathic. Our currently restricted understanding of basic mechanisms driving human gametogenesis severely limits the improvement of clinical care for infertile patients. Using exome sequencing, we identified a nonsense mutation leading to a premature stop in the TEX15 locus (c.2130T>G, p.Y710*) in a consanguineous Turkish family comprising eight siblings in which three brothers were identified as infertile. TEX15 displays testis-specific expression, maps to chromosome 8, contains four exons and encodes a 2789-amino acid protein with uncertain function. The mutation, which should lead to early translational termination at the first exon of TEX15, co-segregated with the infertility phenotype, and our data strongly suggest that it is the cause of spermatogenic defects in the family. All three affected brothers presented a phenotype reminiscent of the one observed in KO mice. Indeed, previously reported results demonstrated that disruption of the orthologous gene in mice caused a drastic reduction in testis size and meiotic arrest in the first wave of spermatogenesis in males while female KO mice were fertile. The data from our study of one Turkish family suggested that the identified mutation correlates with a decrease in sperm count over time. A diagnostic test identifying the mutation in man could provide an indication of spermatogenic failure and prompt patients to undertake sperm cryopreservation at an early age.