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Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure
- Source :
- Hum Genet, Human Genetics, 140, 8, pp. 1169-1182, Repositório Científico de Acesso Aberto de Portugal, Repositório Científico de Acesso Aberto de Portugal (RCAAP), instacron:RCAAP, Human Genetics, 140, 1169-1182
- Publication Year :
- 2021
-
Abstract
- Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266742/pdf/nihms-1705620.pdf GEMINI Consortium: Donald F Conrad, Liina Nagirnaja, Kenneth I Aston, Douglas T Carrell, James M Hotaling, Timothy G Jenkins, Rob McLachlan, Moira K O'Bryan, Peter N Schlegel, Michael L Eisenberg, Jay I Sandlow, Emily S Jungheim, Kenan R Omurtag, Alexandra M Lopes, Susana Seixas, Filipa Carvalho, Susana Fernandes, Alberto Barros, João Gonçalves, Iris Caetano, Graça Pinto, Sónia Correia, Maris Laan, Margus Punab, Ewa Rajpert-De Meyts, Niels Jørgensen, Kristian Almstrup, Csilla G Krausz, Keith A Jarvi. Member of GEMINI Consortium: João Gonçalves (INSA), lista completa na pág 1179. 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. This study was supported by The Eunice Kennedy Shriver NICHD Grant HD080755 (ANY), the Magee-Womens Research Institute University of Pittsburgh Start Up Fund (ANY), PA DoH Grant SAP4100085736 (ANY), NIH P50 Specialized Center Grant HD096723 (KO, ANY, DC, PNS, KH, and MBE), German Research Foundation Clinical Research Unit ‘Male Germ Cells’ grant DFG CRU326 (FT), National Science Centre in Poland, grants no.: 2017/26/D/NZ5/00789 (AM) and 2015/17/B/NZ2/01157; NCN 2020/37/B/NZ5/00549 (MK), Magee-Womens Research Institute University of Pittsburgh, Faculty Fellowship Award and NICHD T32 HD087194 (JH), GM125812 (MB), GM127569 (MB, JLY, and ANY), NIH R00H090289 (MABE), National Health and Medical Research Council Project grant APP1120356 (MKOB, JAV, and DC), UUKi Rutherford Fund Fellowship (BJH), Estonian Research Council, grants IUT34-12 and PRG1021 (ML), and The Netherlands Organization for Scientifc Research grant no.: 918-15-667 as well as an Investigator Award in Science from the Wellcome Trust grant no.: 209451 (JAV). Computational analysis was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. info:eu-repo/semantics/publishedVersion
- Subjects :
- Male
Models, Molecular
Protein Conformation, alpha-Helical
Gene Expression
medicine.disease_cause
Genome
Male infertility
Cohort Studies
Genes, X-Linked
Testis
Testosterone
Genetics (clinical)
Exome sequencing
Spermatogenic Failure
Azoospermia
Genetics
0303 health sciences
Mutation
education.field_of_study
030305 genetics & heredity
Nuclear Proteins
Spermatozoa
3. Good health
Meiosis
Adult
Population
Biology
Genomic Instability
Article
Frameshift mutation
03 medical and health sciences
Exome Sequencing
medicine
Male Infertility
Animals
Humans
Protein Interaction Domains and Motifs
education
Spermatogenesis
Gene
Infertility, Male
030304 developmental biology
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
Base Sequence
Genome, Human
GCNA
Luteinizing Hormone
medicine.disease
Human genetics
Doenças Genéticas
Protein Conformation, beta-Strand
Follicle Stimulating Hormone
Subjects
Details
- ISSN :
- 14321203, 11691182, and 03406717
- Volume :
- 140
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Human genetics
- Accession number :
- edsair.doi.dedup.....8f7d22d59127ca50105d0391444a2052