X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men.
X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men.
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DOI：
10.1056/nejmoa1406192
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发表时间：
2015-05-28
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影响因子：
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通讯作者：
Tüttelmann F
中科院分区：
文献类型：
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作者：
Yatsenko AN;Georgiadis AP;Röpke A;Berman AJ;Jaffe T;Olszewska M;Westernströer B;Sanfilippo J;Kurpisz M;Rajkovic A;Yatsenko SA;Kliesch S;Schlatt S;Tüttelmann F
在大多数不育男性中，非梗阻性无精子症的遗传基础尚不清楚。我们对15例无精子症患者的血液样本进行了阵列比较基因组杂交检测，并对289例无精子症患者和384例对照的血液和精液样本进行了睾丸表达11基因（TEX11）开放阅读框的直接桑格测序进行了突变筛查。我们确定了一个99 kb的染色体Xq13.2，涉及三个TEX11外显子半合子的损失。这种损失，这是相同的2例无精子症，预测减数分裂特异性孢子形成结构域SPO22内的79个氨基酸的缺失。我们随后的突变筛查发现了五个新的TEX11突变：三个剪接突变和两个错义突变。这些突变发生在289例无精子症患者中的7例（2.4%），在384例精子浓度正常的对照组中不存在（P = 0.003）。值得注意的是，在33例（15%）被诊断为无精子症伴减数分裂阻滞的无精子症患者中检测到其中5例TEX11突变。这些患者的减数分裂停滞与Tex11缺陷雄性小鼠的表型相似。免疫组织化学分析显示，正常人睾丸的晚期精母细胞以及圆形和细长的精子细胞中存在特异性细胞质TEX11表达。与此相反，TEX11突变无精子症患者的睾丸减数分裂停滞，缺乏TEX11表达。在我们的研究中，半合子TEX11突变是不育男性减数分裂停滞和无精子症的常见原因。（由美国国立卫生研究院和其他机构资助。
The genetic basis of nonobstructive azoospermia is unknown in the majority of infertile men. We performed array comparative genomic hybridization testing in blood samples obtained from 15 patients with azoospermia, and we performed mutation screening by means of direct Sanger sequencing of the testis-expressed 11 gene (TEX11) open reading frame in blood and semen samples obtained from 289 patients with azoospermia and 384 controls. We identified a 99-kb hemizygous loss on chromosome Xq13.2 that involved three TEX11 exons. This loss, which was identical in 2 patients with azoospermia, predicts a deletion of 79 amino acids within the meiosis-specific sporulation domain SPO22. Our subsequent mutation screening showed five novel TEX11 mutations: three splicing mutations and two missense mutations. These mutations, which occurred in 7 of 289 men with azoospermia (2.4%), were absent in 384 controls with normal sperm concentrations (P = 0.003). Notably, five of those TEX11 mutations were detected in 33 patients (15%) with azoospermia who received a diagnosis of azoospermia with meiotic arrest. Meiotic arrest in these patients resembled the phenotype of Tex11-deficient male mice. Immunohistochemical analysis showed specific cytoplasmic TEX11 expression in late spermatocytes, as well as in round and elongated spermatids, in normal human testes. In contrast, testes of patients who had azoospermia with TEX11 mutations had meiotic arrest and lacked TEX11 expression. In our study, hemizygous TEX11 mutations were a common cause of meiotic arrest and azoospermia in infertile men. (Funded by the National Institutes of Health and others.)