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STAG3 is a strong candidate gene for male infertility

AuthorsLlano, Elena ; Gomez-H, Laura; García-Tuñón, Ignacio; Sánchez-Martín, M.; Caburet, Sandrine; Barbero, José Luis ; Schimenti, John; Veitia, Reiner A.; Pendás, Alberto M.
Issue Date4-Feb-2014
PublisherOxford University Press
CitationHuman Molecular Genetics 23(13): 3421-3431 (2014)
AbstractOligo- and azoospermia are severe forms of male infertility. However, known genetic factors account only for a small fraction of the cases. Recently, whole-exome sequencing in a large consanguineous family with inherited premature ovarian failure (POF) identified a homozygous frameshift mutation in the STAG3 gene leading to a premature stop codon. STAG3encodes a meiosis-specific subunit of the cohesin complex, alarge proteinaceous ring with DNA-entrapping ability that ensures sister chromatid cohesion and enables correct synapsis and segregation of homologous chromosomes during meiosis. The pathogenicity of the STAG3 mutations was functionally validated with a loss- of-function mouse model for STAG3 in oogenesis.However,and sincenone of the male members of this family was homozygous for the mutant allele, we only could hypothesized its putative involvement inmale infertility. In this report,we show that male mice devoid of Stag3 display a severe meiotic phenotype that includes a meiotic arrest at zygonema-like shortening of their chromosome axial elements/lateral elements, partial loss of centromeric cohesion at early prophase and maintenance of the ability to initiate but not complete RAD51- and DMC1-mediated double-strand break repair,demonstrating that STAG3 is a crucial cohesin subunit in mammalian gametogenesis and supporting our proposal that STAG3 is a strong candidate gene for human male infertility. © The Author 2014. Published by Oxford University Press. All rights reserved.
Publisher version (URL)http://dx.doi.org/10.1093/hmg/ddu051
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