A de novo paradigm for male infertility.
A de novo paradigm for male infertility.
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一种男性不育症的全新范式。
DOI：
10.1038/s41467-021-27132-8
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发表时间：
2022-01-10
影响因子：
16.6
通讯作者：
Veltman JA
中科院分区：
文献类型：
--
作者：
Oud MS;Smits RM;Smith HE;Mastrorosa FK;Holt GS;Houston BJ;de Vries PF;Alobaidi BKS;Batty LE;Ismail H;Greenwood J;Sheth H;Mikulasova A;Astuti GDN;Gilissen C;McEleny K;Turner H;Coxhead J;Cockell S;Braat DDM;Fleischer K;D'Hauwers KWM;Schaafsma E;Genetics of Male Infertility Initiative (GEMINI) consortium;Nagirnaja L;Conrad DF;Friedrich C;Kliesch S;Aston KI;Riera-Escamilla A;Krausz C;Gonzaga-Jauregui C;Santibanez-Koref M;Elliott DJ;Vissers LELM;Tüttelmann F;O'Bryan MK;Ramos L;Xavier MJ;van der Heijden GW;Veltman JA
新生突变在偶发性疾病中扮演着重要的角色。我们假设新生突变在严重的男性不育症中起重要作用，并解释了这种未充分研究的疾病的一部分遗传原因。为了验证这一假设，我们对185名不育男性及其未受影响的父母进行了三基外显子组测序。经过系统分析，145例罕见（MAF < 0.1%）蛋白改变的新生突变中有29例被归类为可能导致男性不育表型的原因。我们观察到，与对照组相比，不育男性中功能丧失不耐受基因的新生突变显著增加（p值= 1.00 × 10 - 5）。此外，我们检测到与预测的良性新生突变相比，预测的影响不耐错义基因的致病性新生错义突变显著增加（p值= 5.01 × 10−4）。我们发现的一个基因RBM5是雄性生殖细胞前mrna剪接的重要调节因子，先前在小鼠中与雄性不育有关。在一项后续研究中，在2506名不育患者中观察到6种影响该基因的罕见致病性错义突变，而在5784名有生育能力的男性中，我们没有发现这种突变（p值= 0.03）。我们的结果为新生突变在严重男性不育中的作用提供了证据，并指出了影响生育能力的新候选基因。生殖系新生突变可以影响个体适应性，但它们在人类男性不育中的作用尚未得到充分研究。三基外显子组测序确定了许多影响男性生育能力的新候选基因，包括男性生殖细胞前mrna剪接的必要调节因子。
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. Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing.
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影响因子：
44.1
作者：
Guo J;Grow EJ;Mlcochova H;Maher GJ;Lindskog C;Nie X;Guo Y;Takei Y;Yun J;Cai L;Kim R;Carrell DT;Goriely A;Hotaling JM;Cairns BR
通讯作者：
Cairns BR
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作者：
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Jeanpierre, Cecile
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影响因子：
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作者：
Guo, Fan;Yan, Liying;Qiao, Jie
通讯作者：
Qiao, Jie
影响因子：
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作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G