Identification of potentially damaging amino acid substitutions leading to human male infertility.
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.
Kuzmin
Anastasia
A
Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada.
Jarvi
Keith
K
Lo
Kirk
K
Spencer
Leia
L
Chow
Gary Y C
GY
Macleod
Graham
G
Wang
Qianwei
Q
Varmuza
Susannah
S
D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D053713:Azoospermia / Q000235:genetics; D019295:Computational Biology; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D020224:Expressed Sequence Tags; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics*; D054461:Lim Kinases / Q000235:genetics*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D009845:Oligospermia / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D002787:Sterol Esterase / Q000235:genetics*; D035182:TATA Box Binding Protein-Like Proteins / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; C111446:SBF1 protein, human; D035182:TATA Box Binding Protein-Like Proteins; C441409:TBPL1 protein, human; C102895:LIMK2 protein, human; D054461:Lim Kinases; D002787:Sterol Esterase