RESUMO
De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10-5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10-4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.
Assuntos
Azoospermia/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Mutação com Perda de Função , Mutação de Sentido Incorreto , Oligospermia/genética , Proteínas de Ligação a RNA/genética , Proteínas Supressoras de Tumor/genética , Adulto , Azoospermia/patologia , Estudos de Casos e Controles , Proteínas de Ciclo Celular/deficiência , Proteínas de Ligação a DNA/deficiência , Exoma , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Masculino , Oligospermia/patologia , Proteínas Supressoras de Tumor/deficiência , Sequenciamento do ExomaRESUMO
The aim of this paper is to review the inhibitors of apoptosis proteins, a recently discovered group of caspase inhibitors. We will briefly review the relevance of apoptosis in prostate cancer and some of the control mechanisms, before describing the structure, function and regulation of these molecules. Lastly, we will consider the evidence for the role that IAPs may have in cancer and the implications for prostate cancer in particular. Prostate Cancer and Prostatic Diseases (2001) 4, 28-32
