Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure.
Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure.
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DOI：
10.1007/s00439-021-02287-y
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发表时间：
2021-08
期刊：
影响因子：
5.3
通讯作者：
GEMINI Consortium
中科院分区：
文献类型：
--
作者：
Hardy JJ;Wyrwoll MJ;Mcfadden W;Malcher A;Rotte N;Pollock NC;Munyoki S;Veroli MV;Houston BJ;Xavier MJ;Kasak L;Punab M;Laan M;Kliesch S;Schlegel P;Jaffe T;Hwang K;Vukina J;Brieño-Enríquez MA;Orwig K;Yanowitz J;Buszczak M;Veltman JA;Oud M;Nagirnaja L;Olszewska M;O'Bryan MK;Conrad DF;Kurpisz M;Tüttelmann F;Yatsenko AN;GEMINI Consortium
Male infertility impacts millions of couples yet, the etiology of primary infertility remains largely unknown. A critical element of successful spermatogenesis is maintenance of genome integrity. Here, we present a genomic study of spermatogenic failure (SPGF). Our initial analysis (n = 176) did not reveal known gene-candidates but identified a potentially significant single-nucleotide variant (SNV) in X-linked germ-cell nuclear antigen (GCNA). Together with a larger follow-up study (n = 2049), 7 likely clinically relevant GCNA variants were identified. GCNA is critical for genome integrity in male meiosis and knockout models exhibit impaired spermatogenesis and infertility. Single-cell RNA-seq and immunohistochemistry confirm human GCNA expression from spermatogonia to elongated spermatids. Five identified SNVs were located in key functional regions, including N-terminal SUMO-interacting motif and C-terminal Spartan-like protease domain. Notably, variant p.Ala115ProfsTer7 results in an early frameshift, while Spartan-like domain missense variants p.Ser659Trp and p.Arg664Cys change conserved residues, likely affecting 3D structure. For variants within GCNA’s intrinsically disordered region, we performed computational modeling for consensus motifs. Two SNVs were predicted to impact the structure of these consensus motifs. All identified variants have an extremely low minor allele frequency in the general population and 6 of 7 were not detected in > 5000 biological fathers. Considering evidence from animal models, germ-cell-specific expression, 3D modeling, and computational predictions for SNVs, we propose that identified GCNA variants disrupt structure and function of the respective protein domains, ultimately arresting germ-cell division. To our knowledge, this is the first study implicating GCNA, a key genome integrity factor, in human male infertility.
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影响因子：
16.6
作者：
Maskey, Reeja S.;Kim, Myoung Shin;Baker, Darren J.;Childs, Bennett;Malureanu, Liviu A.;Jeganathan, Karthik B.;Machida, Yuka;van Deursen, Jan M.;Machida, Yuichi J.
通讯作者：
Machida, Yuichi J.
DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
7
作者：
Ng, PC;Henikoff, S
通讯作者：
Henikoff, S
影响因子：
5.8
作者：
Desai, Swapna;Wood-Trageser, Michelle;Rajkovic, Aleksandar
通讯作者：
Rajkovic, Aleksandar