Identification of Potentially Damaging Amino Acid Substitutions Leading to Human Male Infertility
Identification of Potentially Damaging Amino Acid Substitutions Leading to Human Male Infertility
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DOI：
10.1095/biolreprod.109.076000
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发表时间：
2009-08-01
影响因子：
3.6
通讯作者：
Varmuza, Susannah
中科院分区：
文献类型：
--
作者：
Kuzmin, Anastasia;Jarvi, Keith;Varmuza, Susannah
在非梗阻性无精子症或睾丸功能衰竭的男性中发现了许多已知的遗传改变，如Y微缺失和细胞遗传学异常。然而，大多数男性非梗阻性无精子症的病因尚不清楚。本研究的目的是调查原因不明的非梗阻性无精子症的可能性，造成的非同义单核苷酸多态性（SNP）的常染色体基因编码区与精子的生产和生育能力。使用基于小鼠雄性不育遗传学的候选基因方法，我们使用定制的下一代重测序芯片对来自78名显示睾丸衰竭的不育男性的9个常染色体基因进行重测序。数据分析显示，78名不育男性中有14名在9个测序基因中的4个中发现了几个新的杂合非同义SNP。在SBF1中鉴定出8个SNP，在LIMK2中鉴定出3个SNP，在LIPE中鉴定出2个SNP，在TBPL1中鉴定出1个SNP。所有新突变均为杂合构型，表明它们可能是具有显性负性的从头突变。
There are a number of known genetic alterations found in men with nonobstructive azoospermia, or testicular failure, such as Y microdeletions and cytogenetic abnormalities. However, the etiology of nonobstructive azoospermia is unknown in the majority of men. The aim of this study was to investigate the possibility that unexplained cases of nonobstructive azoospermia are caused by nonsynonymous single-nucleotide polymorphisms (SNPs) in the coding regions of autosomal genes associated with sperm production and fertility. Using a candidate gene approach based on genetics of male infertility in mice, we resequenced nine autosomal genes from 78 infertile men displaying testicular failure using custom-made next-generation resequencing chips. Analysis of the data revealed several novel heterozygous nonsynonymous SNPs in four of nine sequenced genes in 14 of 78 infertile men. Eight SNPs in SBF1, three SNPs in LIMK2, two SNPs in LIPE, and one SNP in TBPL1 were identified. All of the novel mutations were in a heterozygous configuration, suggesting that they may be de novo mutations with dominant negative properties.