Novel bi-allelic MSH4 variants causes meiotic arrest and non-obstructive azoospermia.
Novel bi-allelic MSH4 variants causes meiotic arrest and non-obstructive azoospermia.
复制标题
新型双等位基因 MSH4 变异导致减数分裂停滞和非梗阻性无精症
DOI：
10.1186/s12958-022-00900-x
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发表时间：
2022-01-28
期刊：
影响因子：
--
通讯作者：
Yao C
中科院分区：
文献类型：
--
作者：
Li P;Ji Z;Zhi E;Zhang Y;Han S;Zhao L;Tian R;Chen H;Huang Y;Zhang J;Chen H;Zhao F;Zhou Z;Li Z;Yao C
背景
非梗阻性无精子症（NOA）是男性不育中最严重的类型之一，其减数分裂阻滞的遗传原因至今仍不清楚。
方法
四个患有NOA的中国家庭参与了这项研究。我们对四个家系中的四名NOA患者进行了全外显子组测序（WES）。通过桑格测序进一步验证候选致病基因。采用HE染色和免疫组化方法观察NOA患者精子发生的阻滞程度。
结果
我们在4个NOA家系中发现了两个新的MSH4纯合移码突变和两个新的MSH4复合杂合突变。在一个中国血缘家族（NM_002440. 4：c.805_812del：p.V269Qfs*15）中的NOA受影响患者（P9359）和另一个中国家族（NM_002440. 4：c.2220_2223del：p.K741Rfs*2）中的1例NOA患者（P21504）中鉴定出MSH4的纯合功能丧失（LoF）变体。此外，在两个受NOA影响的同胞（P9517和P9517 B）（NM_002440. 4：c.G1950A：p.W650X和c.2179delG：p.D727Mfs*11）和NOA患者（P9540）（NM_002440. 4：c.G244A：p.G82S和c.670delT：p.L224Cfs*3）中鉴定了MSH4的复合杂合变体。组织学分析表明，所有患者的曲细精管中缺乏精子，IHC显示精子发生停滞在减数分裂前期I阶段。与常染色体隐性遗传模式一致，所有这些突变均遗传自杂合子父母携带者。
结论
我们确定了6个新的突变MSH4负责减数分裂阻滞和NOA。这些结果为研究者了解NOA的遗传病因和寻找新的NOA遗传咨询位点提供了新的思路。
Background
Non-obstructive azoospermia (NOA) is one of the most severe type in male infertility, and the genetic causes of NOA with meiotic arrest remain elusive.
Methods
Four Chinese families with NOA participated in the study. We performed whole-exome sequencing (WES) for the four NOA-affected patients in four pedigrees. The candidate causative gene was further verified by Sanger sequencing. Hematoxylin and eosin staining (HE) and immunohistochemistry (IHC) were carried out to evaluate the stage of spermatogenesis arrested in the patients with NOA.
Results
We identified two novel homozygous frameshift mutations of MSH4 and two novel compound heterozygous variants in MSH4 in four pedigrees with NOA. Homozygous loss of function (LoF) variants in MSH4 was identified in the NOA-affected patient (P9359) in a consanguineous Chinese family (NM_002440.4: c.805_812del: p.V269Qfs*15) and one patient with NOA (P21504) in another Chinese family (NM_002440.4: c.2220_2223del:p.K741Rfs*2). Also, compound heterozygous variants in MSH4 were identified in two NOA-affected siblings (P9517 and P9517B) (NM_002440.4: c.G1950A: p.W650X and c.2179delG: p.D727Mfs*11), and the patient with NOA (P9540) (NM_002440.4: c.G244A: p.G82S and c.670delT: p.L224Cfs*3). Histological analysis demonstrated lack of spermatozoa in seminiferous tubules of all patients and IHC showed the spermatogenesis arrested at the meiotic prophase I stage. Consistent with the autosomal recessive mode of inheritance, all of these mutations were inherited from heterozygous parental carriers.
Conclusions
We identified that six novel mutations in MSH4 responsible for meiotic arrest and NOA. And these results provide researchers with a new insight to understand the genetic etiology of NOA and to identify new loci for genetic counselling of NOA.
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影响因子：
3.8
作者：
Manhart CM;Alani E
通讯作者：
Alani E
影响因子：
6.1
作者：
Akbari, Arvand;Padidar, Kimiya;Totonchi, Mehdi
通讯作者：
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影响因子：
6.1
作者：
Ezeh, UIO;Moore, HDM;Cooke, ID
通讯作者：
Cooke, ID
DOI：
10.1073/pnas.96.24.13914
发表时间：
1999-11-23
影响因子：
11.1
作者：
Wang, TF;Kleckner, N;Hunter, N
通讯作者：
Hunter, N
影响因子：
6.1
作者：
van der Bijl, N.;Roepke, A.;Tuettelmann, F.
通讯作者：
Tuettelmann, F.