Pathogenic Anti-Mullerian Hormone Variants in Polycystic Ovary Syndrome
Pathogenic Anti-Mullerian Hormone Variants in Polycystic Ovary Syndrome
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多囊卵巢综合征中的致病性抗苗勒氏管激素变异体
DOI：
10.1210/jc.2017-00612
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发表时间：
2017-08-01
影响因子：
5.8
通讯作者：
Urbanek, Margrit
中科院分区：
文献类型：
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作者：
Gorsic, Lidija K.;Kosova, Gulum;Urbanek, Margrit
内容：多囊卵巢综合征（PCOS）是一种常见的内分泌疾病，是无排卵性不孕的主要原因。目的：考虑到常见疾病易感性变异仅占估计PCOS遗传力的一小部分，我们检验了罕见变异导致遗传力不足的假设。设计、设置和参与者：对80例PCOS患者和24例生殖正常对照者进行无偏全基因组测序（WGS），发现了AMH（编码抗苗勒管激素（AMH）的基因）的潜在有害变体。643例PCOS患者和153例对照患者的AMH靶向测序用于复制WGS findings.Main Outcome Measures：Dual luciferase reporter assays measured the impact of the variants on downstream AMH signaling.Results：我们在PCOS患者和对照组中发现了24种罕见（次要等位基因频率，0.01）AMH变异体; 18种变异体是PCOS女性特有的。18例PCOS特异性变异体中有17例（94%）AMH信号显著降低，而在对照受试者中观察到的6例变异体均未表现出信号的显著缺陷。因此，我们确定了罕见的AMH编码变异，减少AMH介导的信号在一个子集的PCOS患者。结论：据我们所知，这项研究是第一个确定罕见的遗传变异与一个共同的PCOS表型。我们的研究结果表明，减少AMH信号作为PCOS的发病机制。AMH通过抑制CYP 17活性降低雄激素生物合成;因此，AMH变体在PCOS中的潜在作用机制是由于AMH介导的CYP 17活性抑制降低而增加雄激素生物合成。
Context: Polycystic ovary syndrome (PCOS), a common endocrine condition, is the leading cause of anovulatory infertility.Objective: Given that common disease-susceptibility variants account for only a small percentage of the estimated PCOS heritability, we tested the hypothesis that rare variants contribute to this deficit in heritability.Design, Setting, and Participants: Unbiased whole-genome sequencing (WGS) of 80 patients with PCOS and 24 reproductively normal control subjects identified potentially deleterious variants in AMH, the gene encoding anti-Mullerian hormone (AMH). Targeted sequencing of AMH of 643 patients with PCOS and 153 control patients was used to replicate WGS findings.Main Outcome Measures: Dual luciferase reporter assays measured the impact of the variants on downstream AMH signaling.Results: We found 24 rare (minor allele frequency, 0.01) AMH variants in patients with PCOS and control subjects; 18 variants were specific to women with PCOS. Seventeen of 18 (94%) PCOS-specific variants had significantly reduced AMH signaling, whereas none of 6 variants observed in control subjects showed significant defects in signaling. Thus, we identified rare AMH coding variants that reduced AMH-mediated signaling in a subset of patients with PCOS.Conclusion: To our knowledge, this study is the first to identify rare genetic variants associated with a common PCOS phenotype. Our findings suggest decreased AMH signaling as a mechanism for the pathogenesis of PCOS. AMH decreases androgen biosynthesis by inhibiting CYP17 activity; a potential mechanism of action for AMH variants in PCOS, therefore, is to increase androgen biosynthesis due to decreased AMH-mediated inhibition of CYP17 activity.