Year: 2020
Type: dissertation
Abstract: Bardet-Beidl Syndrome (BBS) is a pleiotropic ciliopathy that causes a variety of features in humans and animal models, including retinal degeneration, obesity, male infertility, and intellectual disability. BBS is an autosomal recessive disease and can be caused by mutations in any of 22 known genes. The most common cause of BBS is the M390R mutation in BBS1, which is involved in more than 20% of all cases. In my thesis research, I have investigated the biological basis of BBS-related male infertility and have tested the therapeutic effects of gene supplementation and gene correction in several mouse models of BBS. First, I have shown that male infertility caused by mutations in BBS genes is likely due to the interactions of BBSome proteins with ODF2, a major structural component of spermatozoa flagella. I have also shown that post-natal correction of a BBSome component, BBS8, restores fertility in mice at all time points tested. Using mouse models of BBS1, I have shown that ectopic expression of human BBS1 rescues male infertility in Bbs1M390R/M390R mice. Low expression in the eye and hypothalamus, however, are insufficient to correct retinal degeneration or obesity, respectively. Finally, I have shown that injections of therapeutic vectors for gene therapy and gene correction directly into the testes, or systemically via tail vein and facial vein injection, are insufficient to correct male infertility, retinal degeneration, or obesity in Bbs1M390R/M390R mice. My work has provided insight into the effects of gene supplementation of BBS genes in mouse models, and the results of my experiments can be used to direct future work aimed at treating BBS using gene therapy and gene correction.
DOI: 10.17077/etd.005347
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3199246139