PhD

dissertationMacular degeneration is a debilitating eye disease and is the leading cause of blindness in the developed world affecting both young and old alike. The primary hallmarks of macular degeneration are photoreceptor degeneration and retinal pigment epithelium atrophy in the central retina. An autosomal dominant form of juvenile macular degeneration, Stargardt-like macular dystrophy 3 (STGD3), is caused by mutation in the elongation of very long chain fatty acids protein 4 (ELOVL4). However, little is known about ELOVL4's function or how mutations results in macular degeneration. Genetically manipulated mice expressing a human mutant ELOVL4 protein, containing a premature stop codon in Elov14, or lacking a functional copy of Elov14 are used to investigate both the cause of STGD3 and the function of ELOVL4. Only mice expressing a mutant ELOVL4 protein develop a STGD3-like phenotype, suggestive of a dominant negative cause of STGD3. Elov14 haploinsufficient mice do not develop a STG3-like phenotype further implicating a dominant negative mechanism. Mice without a functional copy of ELov14 die within a few hours after birth, have an impaired skin permeability barrier and fall to produce sufficient C28 and longer chain fatty acids, suggesting an essential role of Elov14 in very long chain fatty acid (>2) elongation. Age-related macular degeneration (AMD) is a complex disease with a poorly understood etiology. Two forms of advanced AMD, geographic atrophy and choroidal neovascularization, represent degenerative processes in the macula that lead to loss of central vision. Soft confluent drusen, characterized by deposits in the macula without visual loss are a precursor of advanced AMD. Based on previous studies in choroidal neovascularization, an expanded Utah cohort is used to analyze the association of a single nucleotide polymosphism in the promoter of HTRA1 with geographic atrophy, and soft confluent drusen. Geographic atrophyp is significantly associated with the A allele in the HTRA1 single nucleotide polymorphism rs11200638. These results increase our understanding of the etiology of AMD and provide a novel gene to investigate for future studies