Homozygous mutations in C14orf39/SIX6OS1 cause non-obstructive azoospermia and premature ovarian insufficiency in humans.
Homozygous mutations in C14orf39/SIX6OS1 cause non-obstructive azoospermia and premature ovarian insufficiency in humans.
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C14orf39/SIX6OS1 的纯合突变会导致人类非梗阻性无精症和卵巢早衰。
DOI：
10.1016/j.ajhg.2021.01.010
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发表时间：
2021-02-04
影响因子：
9.8
通讯作者：
Shi Q
中科院分区：
文献类型：
--
作者：
Fan S;Jiao Y;Khan R;Jiang X;Javed AR;Ali A;Zhang H;Zhou J;Naeem M;Murtaza G;Li Y;Yang G;Zaman Q;Zubair M;Guan H;Zhang X;Ma H;Jiang H;Ali H;Dil S;Shah W;Ahmad N;Zhang Y;Shi Q
人类不孕症是一种多因素疾病，影响全世界8%-12%的育龄夫妇。然而，人类不育的遗传原因仍然知之甚少。联会复合体（SC）是一种保守的三联结构，它将同源染色体连接在一起，在减数分裂过程中起着不可或缺的作用。在这里，我们确定了三个纯合突变SC编码基因C14 orf 39/SIX 6 OS 1在不育的个人从不同的种族人群的全外显子组测序（WES）。这些突变包括移码突变（c.204_205del [p.His68Glnfs 2]），来自一个巴基斯坦近亲家庭，两名男性患有非梗阻性无精子症（NOA），一名女性诊断为卵巢功能不全（POI）以及无义突变（c.958G>T [p.Glu320]）和剪接突变（c.1180−3C>G）。C14 orf 39的突变导致截短的蛋白质保留SYCE 1结合，但表现出受损的C14 ORF 39和SYCE 1之间的多复合物形成。进一步的生殖细胞减数分裂细胞学分析显示，受影响的家族男性与C14 orf 39移码突变显示同源染色体之间的完全不联会，而受影响的中国男性携带的无义或剪接突变显示不完整的联会。NOA和POI在受影响的个人的表型很好地概括Six 6 os 1突变小鼠携带类似的突变。总的来说，我们在人类和小鼠中的发现突出了C14 ORF 39/SIX 6 OS 1在SC组装中的保守作用，并表明本文所述的C14 orf 39/SIX 6 OS 1中的纯合突变是这些受影响个体不育的原因，从而扩大了我们对人类不育遗传基础的理解。
Human infertility is a multifactorial disease that affects 8%–12% of reproductive-aged couples worldwide. However, the genetic causes of human infertility are still poorly understood. Synaptonemal complex (SC) is a conserved tripartite structure that holds homologous chromosomes together and plays an indispensable role in the meiotic progression. Here, we identified three homozygous mutations in the SC coding gene C14orf39/SIX6OS1 in infertile individuals from different ethnic populations by whole-exome sequencing (WES). These mutations include a frameshift mutation (c.204_205del [p.His68Glnfs∗2]) from a consanguineous Pakistani family with two males suffering from non-obstructive azoospermia (NOA) and one female diagnosed with premature ovarian insufficiency (POI) as well as a nonsense mutation (c.958G>T [p.Glu320∗]) and a splicing mutation (c.1180−3C>G) in two unrelated Chinese men (individual P3907 and individual P6032, respectively) with meiotic arrest. Mutations in C14orf39 resulted in truncated proteins that retained SYCE1 binding but exhibited impaired polycomplex formation between C14ORF39 and SYCE1. Further cytological analyses of meiosis in germ cells revealed that the affected familial males with the C14orf39 frameshift mutation displayed complete asynapsis between homologous chromosomes, while the affected Chinese men carrying the nonsense or splicing mutation showed incomplete synapsis. The phenotypes of NOA and POI in affected individuals were well recapitulated by Six6os1 mutant mice carrying an analogous mutation. Collectively, our findings in humans and mice highlight the conserved role of C14ORF39/SIX6OS1 in SC assembly and indicate that the homozygous mutations in C14orf39/SIX6OS1 described here are responsible for infertility of these affected individuals, thus expanding our understanding of the genetic basis of human infertility.
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DOI：
10.1056/nejmoa1309635
发表时间：
2014-03-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Caburet S;Arboleda VA;Llano E;Overbeek PA;Barbero JL;Oka K;Harrison W;Vaiman D;Ben-Neriah Z;García-Tuñón I;Fellous M;Pendás AM;Veitia RA;Vilain E
通讯作者：
Vilain E
冷冻保存对睾丸组织的减数分裂重组和突触没有影响
影响因子：
6.7
作者：
Li, Jianhua;Leng, Mei;Shi, Qinghua
通讯作者：
Shi, Qinghua
影响因子：
13.6
作者：
Sanchez-Saez, Fernando;Gomez-H, Laura;Davies, Owen R.
通讯作者：
Davies, Owen R.
原发性卵巢功能不全的遗传学：新进展和机遇
影响因子：
13.3
作者：
Qin Y;Jiao X;Simpson JL;Chen ZJ
通讯作者：
Chen ZJ
影响因子：
7.2
作者：
Subramanian, Vijayalakshmi V.;Hochwagen, Andreas
通讯作者：
Hochwagen, Andreas