Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa.
Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa.
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DOI：
10.18632/oncotarget.15251
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发表时间：
2017-03-21
期刊：
影响因子：
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通讯作者：
Wang B
中科院分区：
文献类型：
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作者：
Li L;Sha Y;Wang X;Li P;Wang J;Kee K;Wang B
无头精子是一种非常罕见的男性不育疾病。在这个病例中，我们通过全外显子测序鉴定了BRDT基因的一个纯合子突变(c.G2783A，p.G928D)。这种基因产物BRDT是一种睾丸特异性蛋白质，被认为是男性避孕的重要药物靶点。G928D突变位于P-TEFb结合区，介导与转录延伸因子的相互作用，并可能影响下游基因的转录活性。通过对表达BRDT突变的细胞进行RNA测序分析，我们发现与BRDT野生型细胞相比，p.G928D突变蛋白导致了899个基因的错误调控。此外，通过基因本体论分析，P.G928D细胞中上调的基因在细胞内转运、RNA剪接、细胞周期和DNA代谢过程中都有丰富的表达，揭示了导致头精子的病理机制。
Acephalic spermatozoa is a very rare disorder of male infertility. Here, in a patient from from a consanguineous family, we have identified, by whole-exome sequencing, a homozygous mutation (c.G2783A, p.G928D) in the BRDT gene. The gene product, BRDT, is a testis-specific protein that is considered an important drug target for male contraception. The G928D mutation is in the P-TEFb binding domain, which mediates the interaction with transcription elongation factor and might affect the transcriptional activities of downstream genes. By RNA-sequencing analysis of cells expressing the BRDT mutation, we found the p.G928D mutation protein causes mis-regulation of 899 genes compared with BRDT wild-type cells. Furthermore, by Gene Ontology analysis, the upregulated genes in p.G928D cells were enriched in the processes of intracellular transport, RNA splicing, cell cycle and DNA metabolic process, revealing the underlying mechanism of the pathology that leads to acephalic spermatozoa.