Molecular basis of male infertility phenotypes in DCAF17 knockout mice model / Asmaa Mohamed Salem Ali ; Supervised Hassan A. H. Amer , Abdelbary M. Prince , Abdullah M. Assiri

Thesis (M.Sc.) - Cairo University - Faculty of Veterinary Medicine - Department of Biochemistry and Chemistry of Nutrition

DDB1{u2013} and CUL4 {u2013}associated factor 17 (Dcaf17) is a member of DCAF family genes that encode substrate receptor proteins for Cullin-RING E3 ubiquitin ligases (CRLs). CRLs play an important role in diverse cellular processes such as cell proliferation, cell differentiation, DNA replication, DNA repair, gene expression and apoptosis. Proteins encoded by DCAF family genes are predicted to determine specificity of the DDB1-CUL4-E3 ubiquitin ligase complexes. Mutations in Dcaf17 gene in humans causes Woodhouse-Sakati Syndrome (WSS) that is characterized by hypogonadism, alopecia, diabetes, intellectual disability and extrapyramidal symptoms. However, the function of DCAF17 and molecular pathogenesis of WSS are unknown. To unravel the function of DCAF17 and molecular underpinnings of WSS, we performed expression profiling of Dcaf17 in different tissues of wild type mouse by qRT-PCR and generated Dcaf17 knockout mice by targeted deletion that resulted into disruption of exon 4 of Dcaf17 gene. Expression profiling of Dcaf17 showed that it is highly expressed in testis with low level of expression in brain, liver, skin and pancreas. Analyses of Dcaf17 mRNA transcripts in post-natal mice testis revealed that its level increased by 4, 7 and 9-fold at 14, 23 and 32 PND, respectively. Although Dcaf17 disruption did not have any effect on female fertility, Dcaf17 deletion led to male infertility with severe defects in sperm morphology with normal testicular mass. This male infertility resulted from decreased number of spermatozoa, reduced sperm motility and abnormal sperm morphology resulting from disrupted nuclei, displacement of acrosome and mid piece with disorganization of the mitochondrial sheath. Histological examination of the mutant testis showed impaired spermatogenesis with vacuoles in the seminiferous tubules and presence of degenerated sloughed germ cells and increased cell apoptosis at various stages

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