Functional polymorphism in H2BFWT‐5′UTR is associated with susceptibility to male infertility

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Abstract
H2B histone family, member W, testis‐specific (H2BFWT) gene encodes a testis‐specific histone that becomes incorporated into sperm chromatin. A male infertility‐associated single nucleotide polymorphism (−9C > T) within the 5′ untranslated region (5′UTR) of the H2BFWT gene was identified by direct sequencing. Statistical association studies showed the polymorphism significantly associated with male infertility (n= 442, P= 0.0157), especially in non‐azoospermia (n= 262, P= 0.018). Furthermore, this polymorphism is also associated with sperm parameters, especially sperm count (n= 164, P= 0.0127) and vitality (n= 164, P= 0.0076). We investigated how the genetic variant at 5′UTR confers susceptibility to non‐azoospermia. Western blotting of His‐tag H2BFWT revealed a difference at the translational level between ‐9T and the wild‐type −9C in the absence of change at the transcriptional level. Reporter assays showed that this reducing translational change originated from an upstream open reading frame (uORF) generated by the −9C to −9T change. Finally, in vivo H2BFWT expression in sperm was significantly dependent on the −9C > T genotype from non‐azoospermia (P= 0.0061). Therefore, this polymorphism could affect the translational efficiency of a quantitatively important histone protein by the uORF. Our data implicate H2BFWT as a susceptibility factor for male infertility, possibly with other genetic and environmental factors.

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