Open AccessFunctional polymorphism in H2BFWT‐5′UTR is associated with susceptibility to male infertility
Author(s) -
Lee Jinu,
Park Hee Suk,
Kim Hwan Hee,
Yun YeoJin,
Lee Dong Ryul,
Lee Suman
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00830.x
Subject(s) - male infertility , biology , azoospermia , genetics , untranslated region , genotype , infertility , chromatin , sperm , histone , single nucleotide polymorphism , gene , microbiology and biotechnology , messenger rna , pregnancy
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.