Nephronophthisis is a genetic cystic kidney disease. There are numerous extrarenal manifestations of the disease. One of the most common associated pathologies of nephronophthisis is the development of retinal degeneration (Retinitis Pigmentosa or Leber Congenital Amaurosis). This clinical finding involving the kidneys and the retina is given the diagnosis of Senior-Loken syndrome. Development of nephronophthisis has been attributed primarily to mutations in several nephrocystin proteins, which are thought to be important in the development and normal function of the primary cilium in cells. Interestingly, mutations in NPHP5 have been found in virtually all Senior-Loken syndrome patients. However, it is still currently not known what the normal function of NPHP5 and how NPHP5 mutations contribute to retinal degeneration. The goal of this thesis project is to establish both in vivo an in vitro models to study the normal role of NPHP5 as it relates to development of retinal degeneration.
The first aim i s to develop a conditional knock out of NPHP5 in rod photoreceptor cells of mice to understand how absence of the protein may lead to development of retinitis pigmentosa-like retinal degeneration.
The second aim i s to investigate the role of NPHP5 in its predicted role of controlling cellular polarity in an in vitro cell culture system. ! !
Senior-Loken syndrome is a debilitating disease that affects the kidneys and the retina. Disease affecting the retina is a progressive degeneration of photoreceptors of the eye called Retinitis Pigmentosa (RP). Currently, there is no cure for RP. Mutations in the gene, NPHP5, cause Senior-Loken syndrome. This project proposal aims to understand how mutations in NPHP5 lead to retinal degeneration. This is very relevant to society as it will determine specific mechanisms leading to disease and potentially discover new targets for pharmacological treatment of RP.
|Ronquillo, C C; Bernstein, P S; Baehr, W (2012) Senior-Løken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis. Vision Res 75:88-97|