Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest
Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest
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DOI：
10.1093/humrep/dez204
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发表时间：
2019-11-01
影响因子：
6.1
通讯作者：
Tuettelmann, F.
中科院分区：
文献类型：
--
作者：
van der Bijl, N.;Roepke, A.;Tuettelmann, F.
研究问题：基质抗原3（STAG 3）基因序列变异是男性不育患者非梗阻性无精子症（NOA）的原因吗？简要答复：影响STAG 3蛋白功能的序列变异导致男性不育，原因是减数分裂停滞。已知：在女性和男性中，STAG 3编码减数分裂特异性蛋白，对减数分裂粘附素复合物的功能至关重要。STAG 3的序列变异已被报道会导致雄性和雌性小鼠的减数分裂停滞和人类女性的卵巢早衰，但迄今为止不会导致不育的人类男性。研究设计，规模，持续时间：STAG 3的完整编码区直接在一个队列中测序28名NOA男性由于减数分裂停滞。此外，对一个更大的275名接受全外显子组测序（WES）的不育男性进行了潜在STAG 3序列变异的筛选。此外，减数分裂的蔓延，免疫组化，WES和人口抽样概率（PSAP）已进行的索引case.PARTICIPANTS/MATERIALS，设置，方法：本研究包括28个不育，但在其他方面健康的人类男性谁进行桑格测序的STAG 3的完整编码区。此外，已经筛选了具有不同不育表型的275名不育人类男性的WES数据的相关STAG 3变体。所有受试者均提前进行染色体核型分析和无精子因子（AZF）筛查。在索引患者中，分离分析，WES数据，PSAP，实验室参数，睾丸组织学和核扩散已被添加到支持的findings.Main结果和机会的作用：两个化合物杂合变体在STAG 3（c。[1262T>G];[1312C>T]，p. [（Leu 421 Arg）];[（Arg 438 Ter）]）在其他方面健康的人类男性中由于完全的双侧减数分裂停滞而导致男性不育。通过对父母和患者兄弟的桑格测序证实了复合杂合性。通过分析患者的WES数据和应用PSAP管道，排除了可能影响精子发生的其他变体。正如Stag 3基因敲除小鼠减数分裂扩散所预期的那样，生殖细胞在偶线期后没有进一步发育，并显示出严重的染色体畸变。在275例其他表型的不育男性中未发现STAG 3的罕见变异。我们的研究结果表明，STAG 3变异体对其蛋白功能产生负面影响是NOA的罕见原因（
STUDY QUESTION: Are sequence variants in the stromal antigen 3 (STAG3) gene a cause for non-obstructive azoospermia (NOA) in infertile human males?SUMMARY ANSWER: Sequence variants affecting protein function of STAG3 cause male infertility due to meiotic arrest.WHAT IS KNOWN ALREADY: In both women and men, STAG3 encodes for a meiosis-specific protein that is crucial for the functionality of meiotic cohesin complexes. Sequence variants in STAG3 have been reported to cause meiotic arrest in male and female mice and premature ovarian failure in human females, but not in infertile human males so far.STUDY DESIGN, SIZE, DURATION: The full coding region of STAG3 was sequenced directly in a cohort of 28 men with NOA due to meiotic arrest. In addition, a larger group of 275 infertile men that underwent whole-exome sequencing (WES) was screened for potential STAG3 sequence variants. Furthermore, meiotic spreads, immunohistochemistry, WES and population sampling probability (PSAP) have been conducted in the index case.PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included 28 infertile but otherwise healthy human males who underwent Sanger sequencing of the full coding region of STAG3. Additionally, WES data of 275 infertile human males with different infertility phenotypes have been screened for relevant STAG3 variants. All participants underwent karyotype analysis and azoospermia factor (AZF) screening in advance. In the index patient, segregation analysis, WES data, PSAP, lab parameters, testis histology and nuclear spreads have been added to suplort the findings.MAIN RESULTS AND THE ROLE OF CHANCE: Two compound-heterozygous variants in STAG3 (c.[1262T>G];[1312C>T], p.[(Leu421Arg)];[(Arg438Ter)]) have been found to cause male infertility due to complete bilateral meiotic arrest in an otherwise healthy human male. Compound heterozygosity was confirmed by Sanger sequencing of the parents and the patient's brother. Other variants which may affect spermatogenesis have been ruled out through analysis of the patient's WES data and application of the PSAP pipeline. As expected from Stag3 knockout-mice meiotic spreads, germ cells did not develop further than zygotene and showed drastic chromosome aberrations. No rare variants in STAG3 were found in the 275 infertile males with other phenotypes. Our results indicate that STAG3 variants that negatively affect its protein function are a rare cause of NOA (