Autor(es):
Hardy, Jimmaline J. ; Wyrwoll, Margot J. ; Mcfadden, William ; Malcher, Agnieszka ; Rotte, Nadja ; Pollock, Nijole C. ; Munyoki, Sarah ; Veroli, Maria V. ; Houston, Brendan J. ; Xavier, Miguel J. ; Kasak, Laura ; Punab, Margus ; Laan, Maris ; Kliesch, Sabine ; Schlegel, Peter ; Jaffe, Thomas ; Hwang, Kathleen ; Vukina, Josip ; Brieño-Enríquez, Miguel A. ; Orwig, Kyle ; Yanowitz, Judith ; Buszczak, Michael ; Veltman, Joris A. ; Oud, Manon ; Nagirnaja, Liina ; Olszewska, Marta ; O’Bryan, Moira K. ; Conrad, Donald F. ; Kurpisz, Maciej ; Tüttelmann, Frank ; Yatsenko, Alexander N. ; Conrad, Donald F. ; Nagirnaja, Liina ; Aston, Kenneth I. ; Carrell, Douglas T. ; Hotaling, James M. ; Jenkins, Timothy G. ; McLachlan, Rob ; O’Bryan, Moira K. ; Schlegel, Peter N. ; Eisenberg, Michael L. ; Sandlow, Jay I. ; Jungheim, Emily S. ; Omurtag, Kenan R. ; Lopes, Alexandra M. ; Seixas, Susana ; Carvalho, Filipa ; Fernandes, Susana ; Barros, Alberto ; Gonçalves, João ; Caetano, Iris ; Pinto, Graça ; Correia, Sónia ; Laan, Maris ; Punab, Margus ; Meyts, Ewa Rajpert-De ; Jørgensen, Niels ; Almstrup, Kristian ; Krausz, Csilla G. ; Jarvi, Keith A. ; on behalf of GEMINI Consortium
Data: 2021
Identificador Persistente: http://hdl.handle.net/10400.18/7938
Origem: Repositório Científico do Instituto Nacional de Saúde
Assunto(s): Male Infertility; GCNA; Spermatogenic Failure; Doenças Genéticas
Descrição
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 identifed a potentially signifcant 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 identifed. GCNA is critical for genome integrity in male meiosis and knockout models exhibit impaired spermatogenesis and infertility. Single-cell RNA-seq and immunohistochemistry confrm human GCNA expression from spermatogonia to elongated spermatids. Five identifed 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 afecting 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 identifed 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-specifc expression, 3D modeling, and computational predictions for SNVs, we propose that identifed GCNA variants disrupt structure and function of the respective protein domains, ultimately arresting germ-cell division. To our knowledge, this is the frst study implicating GCNA, a key genome integrity factor, in human male infertility.
