Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure
Por:
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, Brieno-Enriquez, MA, Orwig, K, Yanowitz, J, Buszczak, M, Veltman, JA, Oud, M, Nagirnaja, L, Olszewska, M, O'Bryan, MK, Conrad, DF, Kurpisz, M, Tuttelmann, F, Yatsenko, AN, Krausz C.G., GEMINI Consortium
Publicada:
1 ago 2021
Ahead of Print:
1 may 2021
Resumen:
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.
Filiaciones:
Hardy, JJ:
Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Magee Womens Res Inst, Pittsburgh, PA 02115 USA
Wyrwoll, MJ:
Univ Munster, Inst Reprod Genet, Munster, Germany
Mcfadden, W:
Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Magee Womens Res Inst, Pittsburgh, PA 02115 USA
Malcher, A:
Polish Acad Sci, Inst Human Genet, Poznan, Poland
Rotte, N:
Univ Munster, Inst Reprod Genet, Munster, Germany
Pollock, NC:
Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Magee Womens Res Inst, Pittsburgh, PA 02115 USA
Munyoki, S:
Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Magee Womens Res Inst, Pittsburgh, PA 02115 USA
Veroli, MV:
Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Magee Womens Res Inst, Pittsburgh, PA 02115 USA
Houston, BJ:
Univ Melbourne, Sch Biosci, Parkville, Vic, Australia
Punab, M:
Univ Tartu, Inst Clin Med, Tartu, Estonia
Univ Tartu, Inst Biomed & Translat Med, Tartu, Estonia
Laan, M:
Weill Cornell Med, Dept Urol, New York, NY USA
Kliesch, S:
Ctr Reprod Med & Androl, Dept Clin & Surg Androl, Munster, Germany
Schlegel, P:
Newcastle Univ, Biosci Inst, Fac Med Sci, Newcastle Upon Tyne, Tyne & Wear, England
Jaffe, T:
West Virginia Univ, Dept Urol, Sch Med, Morgantown, WV 26506 USA
Hwang, K:
Univ Pittsburgh, Sch Med, Dept Urol, Pittsburgh, PA USA
Vukina, J:
Univ Pittsburgh, Sch Med, Dept Urol, Pittsburgh, PA USA
Brieno-Enriquez, MA:
Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Magee Womens Res Inst, Pittsburgh, PA 02115 USA
Orwig, K:
Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Magee Womens Res Inst, Pittsburgh, PA 02115 USA
Yanowitz, J:
Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Magee Womens Res Inst, Pittsburgh, PA 02115 USA
Buszczak, M:
Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA
Radboud Univ Nijmegen, Dept Human Genet, Donders Inst Brain Cognit & Behav, Med Ctr, Nijmegen, Netherlands
Oud, M:
Univ Texas Southwestern Med Ctr Dallas, Ctr Regenerat Sci & Med, Dallas, TX 75390 USA
Oregon Hlth & Sci Univ, Dept Genet, Oregon Natl Primate Res Ctr, Beaverton, OR USA
Olszewska, M:
Polish Acad Sci, Inst Human Genet, Poznan, Poland
O'Bryan, MK:
Univ Melbourne, Sch Biosci, Parkville, Vic, Australia
Conrad, DF:
Tartu Univ Hosp, Androl Ctr, Tartu, Estonia
Kurpisz, M:
Polish Acad Sci, Inst Human Genet, Poznan, Poland
Tuttelmann, F:
Univ Munster, Inst Reprod Genet, Munster, Germany
Yatsenko, AN:
Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Magee Womens Res Inst, Pittsburgh, PA 02115 USA
Krausz C.G.:
Fundacio Puigvert, Barcelona, Spain
Institut dInvestigació Biomèdica Sant Pau IIB Sant Pau, Barcelona, Spain
Green Accepted
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