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Novel Biallelic DNAH1 Variations Cause Multiple Morphological Abnormalities of the Sperm Flagella
DNA and Cell Biology ( IF 3.1 ) Pub Date : 2021-06-08 , DOI: 10.1089/dna.2021.0097
Hua-Ying Hu 1, 2 , Tian-Ying Wei 2 , Zhan-Ke Feng 2 , Song-Jun Li 3 , Rong Zhao 2 , Xiao-Ling Yi 3 , Ti-Ling Hu 2 , Huan Zhao 3 , Cun-Xi Li 2 , Zu-Guo Liu 1, 4, 5
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Sperm motility is vital to human reproduction, and malformed sperm flagella can cause male infertility. Individuals with multiple morphological abnormalities of the flagella mostly have absent, short, coiled, bent, and/or irregular-caliber flagella. In this study, a patient with male infertility underwent a physical examination along with his wife. Genetic testing was performed by whole-exome sequencing of the couple, and Sanger sequencing was performed for validation. Novel biallelic variations in the DNAH1: (NM_015512.4) gene consisting of c.1336G>C (p.E446Q) and c.2912G>A (p.R971H) were identified. In silico structural analysis revealed that the amino acid residues affected by the variation were evolutionarily conserved, and the variant p.R971H influenced the stability of the DNAH1 protein. Morphological studies of the patient's sperm showed defects in its flagella. Results of Papanicolaou staining and scanning electron microscopy demonstrated coiled and short flagella with multiple anomalies. Transmission electron microscopy of the sperm flagella showed that the inner dynein arm and radial spoke were absent, and the dense fiber and microtubule doublets were displaced. Quantitative PCR of the mRNA of the patient's sperm showed that the expression of DNALI1 was dramatically reduced. Collectively, these findings elucidated the genetic cause of the family's infertility and provided insight into the functioning of the DNAH1 gene.

中文翻译:

新的双等位基因 DNAH1 变异导致精子鞭毛的多种形态异常

精子活力对人类生殖至关重要,畸形的精子鞭毛会导致男性不育。具有多种鞭毛形态异常的个体大多具有缺失、短、卷曲、弯曲和/或不规则口径的鞭毛。在这项研究中,一名男性不育患者与他的妻子一起接受了体检。通过对这对夫妇的全外显子组测序进行基因检测,并进行 Sanger 测序进行验证。鉴定了由 c.1336G>C (p.E446Q) 和 c.2912G>A (p.R971H) 组成的DNAH1 : (NM_015512.4) 基因中的新双等位变异。电脑模拟结构分析表明,受变异影响的氨基酸残基在进化上是保守的,变体p.R971H影响了DNAH1蛋白的稳定性。对患者精子的形态学研究显示其鞭毛有缺陷。Papanicolaou 染色和扫描电子显微镜的结果表明,鞭毛呈卷曲和短小,有多个异常。精子鞭毛透射电镜显示内动力蛋白臂和径向辐条缺失,致密纤维和微管双联体移位。患者精子mRNA的定量PCR显示DNALI1的表达被大大减少了。总的来说,这些发现阐明了家庭不育的遗传原因,并提供了对DNAH1基因功能的深入了解。
更新日期:2021-06-09
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