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Hum Mol Genet. 2014 Jul 1;23(13):3421-31. doi: 10.1093/hmg/ddu051. Epub 2014 Mar 7.

STAG3 is a strong candidate gene for male infertility.

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Departamento de Fisiología y Farmacología and
Instituto de Biología Molecular y Celular del Cáncer (CSIC-USAL), 37007 Salamanca, Spain.
Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain.
Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France Université Paris Diderot-Paris 7, 75205 Paris Cedex 13, France.
Centro de Investigaciones Biológicas (CSIC), Madrid 28040, Spain and.
Center for Vertebrate Genomics, Cornell University, Ithaca, NY 14850, USA.
Instituto de Biología Molecular y Celular del Cáncer (CSIC-USAL), 37007 Salamanca, Spain


Oligo- 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. STAG3 encodes a meiosis-specific subunit of the cohesin complex, a large 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 since none of the male members of this family was homozygous for the mutant allele, we only could hypothesized its putative involvement in male 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.

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