title: Deficiency in Outer Dense Fiber 1 Is a Marker and Potential Driver of Idiopathic Male Infertility.
abstract: Globally, ∼1 in 15 men of reproductive age are infertile, yet the precise mechanisms underlying their gamete failure are unknown. Although a semen analysis is performed to determine fertilizing potential, the diagnostic suitability of this analysis has been questioned in several reports, as many men, classified as infertile according to their semen analysis, subsequently turn out to be fertile. Herein, we have used a quantitative (phospho)-proteomic analysis, using enrichment on titanium dioxide followed by ion-trap mass spectrometry (LC-MS/MS), to compare the semen of infertile versus fertile males. One protein, namely outer dense fiber 1 (ODF1), was dramatically reduced in infertile males. Using specific antibodies, we then screened the gametes of a cohort of suspected infertile men and demonstrated a reduction in the amount of ODF1 compared with fertile controls. Stress treatment of sperm deficient in ODF1 caused the head to decapitate, suggesting why these gametes fail to initiate fertilization. Interestingly, electron micrographs of ODF1-deficient spermatozoa revealed an abnormal connecting piece, indicating several developmental defects with both the implantation plate and the thin laminated fibers. In some cases, the implantation plate appeared to be reduced in size or was overburdened by granular material near the connecting piece. Hence, a strong reduction ODF1 is a marker of idiopathic male infertility and a potential driver of this condition.
authors: From the ‡Discipline of Biological Sciences, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute,University of Newcastle, Callaghan, NSW 2308, Australia.
authors: Louise
authors: L
authors: Hetherington
authors: §Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Vic, 3052, Australia.
authors: Elena K
authors: EK
authors: Schneider
authors: Caroline
authors: C
authors: Scott
authors: ¶Department of Anatomy and Developmental Biology, Monash University, Vic, 3800, Australia; Department of Urology 356510, University of Washington, Seattle WA 98195-6510, USA.
authors: David
authors: D
authors: DeKretser
authors: Charles H
authors: CH
authors: Muller
authors: Hubert
authors: H
authors: Hondermarck
authors: §Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Vic, 3052, Australia.
authors: Tony
authors: T
authors: Velkov
authors: From the ‡Discipline of Biological Sciences, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute,University of Newcastle, Callaghan, NSW 2308, Australia; mark.baker@newcastle.edu.au.
authors: Mark A
authors: MA
authors: Baker
mesh_terms: D000328:Adult; D002853:Chromatography, Liquid; D015536:Down-Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007248:Infertility, Male / Q000378:metabolism*; D008297:Male; D010750:Phosphoproteins / Q000032:analysis*; D040901:Proteomics / Q000379:methods*; D012661:Semen / Q000502:physiology*; D055101:Semen Analysis; D013077:Sperm Head / Q000378:metabolism; D013081:Sperm Motility; D053719:Tandem Mass Spectrometry
chemical_list: D006360:Heat-Shock Proteins; C086058:ODF1 protein, human; D010750:Phosphoproteins