title: UBE2B mRNA alterations are associated with severe oligozoospermia in infertile men.
abstract: Oligozoospermia (low sperm count) is a common semen deficiency. However, to date, few genetic defects have been identified to cause this condition. Moreover, even fewer molecular genetic diagnostic tests are available for patients with oligozoospermia in the andrology clinic. Based on animal and gene expression studies of oligozoospermia, several molecular pathways may be disrupted in post-meiotic spermatozoa. One of the disrupted pathways is protein ubiquitination and cell apoptosis. A critical protein involved in this pathway is the ubiquitin-conjugating enzyme 2B, UBE2B. Absence of Ube2b in male mice causes spermatogenic meiotic disruption with increased apoptosis, leading to infertility. To examine the association between messenger RNA defects in UBE2B and severe oligozoospermia (0.1-10 × 10(6) cells/ml), sequencing of sperm cDNA in 326 oligozoospermic patients and 421 normozoospermic men was performed. mRNA alterations in UBE2B were identified in sperm in 4.6% (15 out of 326) of the oligozoospermic patients, but not found in control men, suggesting strong association between mRNA defects and oligozoospermia (χ(2) = 19, P = 0.0001). Identified UBE2B alterations include nine splicing, four missense and two nonsense alterations. The follow-up screen of corresponding DNA regions did not reveal causative DNA mutations, suggesting a post-transcriptional nature of identified defects. None of these variants were reported in the dbSNP database, although other splicing abnormalities with low level of expression were present in 11 out of 421 (2.6%) controls. Our findings suggest that two distinct molecular mechanisms, mRNA editing and splicing processing, are disrupted in oligozoospermia. We speculate that the contribution of post-transcriptional mRNA defects to oligozoospermia could be greater than previously anticipated.
authors: Department of OBGYN, School of Medicine, University of Pittsburgh, PA 15213, USA. yatsenkoan@mwri.magee.edu
authors: Alexander N
authors: AN
authors: Yatsenko
authors: Andrew P
authors: AP
authors: Georgiadis
authors: Lata J
authors: LJ
authors: Murthy
authors: Dolores J
authors: DJ
authors: Lamb
authors: Martin M
authors: MM
authors: Matzuk
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D009845:Oligospermia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017393:RNA Editing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013094:Spermatozoa / Q000378:metabolism* / Q000473:pathology; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D012333:RNA, Messenger; C471546:UBE2B protein, human; D044763:Ubiquitin-Conjugating Enzymes
keywords: UBE2B alterations; abnormal splicing; male infertility; oligozoospermia; post-transcriptional errors
references: Nat Genet. 2007 May;39(5):661-5
references: 17435757
references: N Engl J Med. 2012 May 10;366(19):1803-13
references: 22559061
references: Nat Med. 2008 Nov;14(11):1197-213
references: 18989307
references: Mol Hum Reprod. 2012 Jan;18(1):14-21
references: 21911476
references: J Mol Med (Berl). 2009 Jul;87(7):735-48
references: 19466390
references: Acta Obstet Gynecol Scand. 2004 Nov;83(11):1071-8
references: 15488125
references: Nat Cell Biol. 2002 Oct;4 Suppl:s41-9
references: 12479614
references: J Urol. 2010 Apr;183(4):1636-42
references: 20172548
references: Hum Genet. 1983;65(2):185-8
references: 6654332
references: N Engl J Med. 2001 Nov 8;345(19):1388-93
references: 11794171
references: Asian J Androl. 2008 May;10(3):461-6
references: 18385908
references: Science. 1989 Sep 8;245(4922):1066-73
references: 2475911
references: FASEB J. 2010 Apr;24(4):981-93
references: 19940261
references: Fertil Steril. 2006 Mar;85(3):629-34
references: 16500330
references: Nature. 2004 May 13;429(6988):154
references: 15141202
references: PLoS Biol. 2009 Feb 24;7(2):e44
references: 19243224
references: PLoS Genet. 2010 Dec 09;6(12):e1001236
references: 21151575
references: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12201-6
references: 14526100
references: J Androl. 2008 Sep-Oct;29(5):564-71
references: 18497339
references: Science. 2011 Jul 1;333(6038):53-8
references: 21596952
references: Mol Cell Biol. 2003 Feb;23(4):1151-62
references: 12556476
references: PLoS One. 2012;7(10):e47892
references: 23112866
references: Hum Reprod. 2005 Feb;20(2):437-42
references: 15567875
references: Mol Reprod Dev. 2003 Jul;65(3):298-308
references: 12784252
references: Hum Genet. 1984;66(2-3):162-4
references: 6714975
references: Fertil Steril. 2012 Feb;97(2):275-81
references: 22289287
references: Hum Mol Genet. 2009 Apr 1;18(7):1301-9
references: 19147683
references: Hum Mol Genet. 2007 Apr 1;16(7):763-73
references: 17327269
references: Fertil Steril. 2009 Jun;91(6):2466-70
references: 18439586
references: PLoS One. 2012;7(10):e44479
references: 23071498
references: Cell. 1996 Sep 6;86(5):799-810
references: 8797826
references: Asian J Androl. 2011 Jan;13(1):139-51
references: 21057516
references: J Cell Sci. 2007 Jun 1;120(Pt 11):1841-51
references: 17488778
references: BMC Genomics. 2010 Jun 10;11:367
references: 20537150
references: Cytogenet Genome Res. 2003;103(3-4):225-34
references: 15051943
references: Nat Clin Pract Urol. 2007 Sep;4(9):460-1
references: 17684507
references: JAMA. 1992 Apr 1;267(13):1794-7
references: 1545465
references: Asian J Androl. 2011 Jan;13(1):53-8
references: 21102478
references: Fertil Steril. 2005 Nov;84(5):1308-15
references: 16275219
references: Hum Mol Genet. 2006 Dec 1;15(23):3411-9
references: 17047026