Paediatrics (RCH) - Theses

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    The role of the Parkin Co-Regulated Gene (PACRG) in male infertility
    Wilson, Gabrielle R. ( 2009)
    A leading cause of male infertility is genetic variation in genes required for sperm formation and/or function. There is evidence to suggest PACRG is involved in mammalian spermatogenesis. Specifically, the loss of Pacrg function causes a spermatogenic defect and male infertility in mice. To investigate if PACRG plays a similar role in human spermatogenesis, the localisation of PACRG was determined in human testis. Using an immunohistochemical approach, this study demonstrated that PACRG is localised to the human sperm flagella. To investigate a potential role for PACRG in human male infertility, sequence analysis and an association study were performed. Sequence analysis did not identify any pathological alterations. However, 1 of 3 variants identified (rs9347683) was shown to be significantly associated with male infertility by association analysis (p=0.009, Odds Ratio=1.6, n=766). A high degree of structural and functional conservation exists between different types of motile cilia/flagella. Evidence from studies in C.reinhardtii and T.brucei indicate Pacrg is necessary for axoneme formation and microtubule stability. To test the role of the mammalian homologue, this study characterised the Pacrg knockout mouse, quakingviable (qkv) and generated Pacrg transgenic qkv mice (qkv-Tg). Using immunohistochemistry and immunoelectron microscopy this study demonstrated that Pacrg was localised to the axonemal microtubule doublets of sperm and ependymal cilia. The absence of Pacrg was associated with compromised sperm flagella formation and male infertility. In addition, histological and MRI analysis of qkv mutant mice revealed hydrocephalus. Specifically, qkv mutant mice showed a ~2.5 fold expansion of the lateral ventricle area compared to wildtype mice. The hydrocephalus phenotype was associated with a reduction in ependymal cilial beat frequency (CBF). Transgenic expression of Pacrg was sufficient to rescue the hydrocephalus and infertility phenotypes. In conclusion, this study has demonstrated that Pacrg is a novel axonemal protein in a subset of motile cilia and loss of Pacrg function results in spermiogenic defects and hydrocephalus in mice. Further, this study has shown that variations in the human PACRG promoter are a risk factor in human male infertility. Collectively these data provide evidence for a conserved role of PACRG in the cilial axoneme. This suggests the protein may be a candidate for a variety of human diseases characterised by cilial dysfunction.