Faculty Collaboration Database

Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure. Hum Genet 2021 Aug;140(8):1169-1182

Date

05/09/2021

Pubmed ID

33963445

Pubmed Central ID

PMC8266742

DOI

10.1007/s00439-021-02287-y

Scopus ID

2-s2.0-85105426534 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

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.

Author List

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

Author

Jay I. Sandlow MD Chair, Professor in the Urologic Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Animals
Azoospermia
Base Sequence
Cohort Studies
Follicle Stimulating Hormone
Gene Expression
Genes, X-Linked
Genome, Human
Genomic Instability
Humans
Infertility, Male
Luteinizing Hormone
Male
Meiosis
Models, Molecular
Mutation
Nuclear Proteins
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Spermatogenesis
Spermatozoa
Testis
Testosterone