title: Functional polymorphism in H2BFWT-5'UTR is associated with susceptibility to male infertility.
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.
authors: Department of Pharmacology, CHA Stem Cell Institute, School of Medicine, CHA University, Kyunggi-Do, Korea.
authors: Jinu
authors: J
authors: Lee
authors: Functional Genomics Lab, CHA Stem Cell Institute, School of Medicine, CHA University, Kyunggi-Do, Korea.
authors: Hee Suk
authors: HS
authors: Park
authors: Functional Genomics Lab, CHA Stem Cell Institute, School of Medicine, CHA University, Kyunggi-Do, Korea.
authors: Hwan Hee
authors: HH
authors: Kim
authors: Functional Genomics Lab, CHA Stem Cell Institute, School of Medicine, CHA University, Kyunggi-Do, Korea.
authors: Yeo-Jin
authors: YJ
authors: Yun
authors: Fertility Center of CHA General Hospital, CHA Stem Cell Institute, School of Medicine, CHA University, Seoul, Korea.
authors: Dong Ryul
authors: DR
authors: Lee
authors: Functional Genomics Lab, CHA Stem Cell Institute, School of Medicine, CHA University, Kyunggi-Do, Korea.|Department of Pharmacology, CHA Stem Cell Institute, School of Medicine, CHA University, Kyunggi-Do, Korea.
authors: Suman
authors: S
authors: Lee
mesh_terms: D020121:5' Untranslated Regions; D001483:Base Sequence; D015153:Blotting, Western; D016022:Case-Control Studies; D017931:DNA Primers; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
chemical_list: D020121:5' Untranslated Regions; D017931:DNA Primers