Personnel: Stephanie Hagstrom, Gayle Pauer, Umadevi Narendra and Quansheng Xi
(a) New Genes Causing Leber's Congenital Amaurosis and RP Leber's congenital amaurosis (LCA) is a clinically heterogeneous group of childhood retinal degenerations generally reported to be inherited in an autosomal recessive manner. LCA is the earliest and most severe form of inherited retinal degeneration and accounts for at least 5% of all inherited retinal dystrophies. This disease is usually recognized at birth or shortly after. Like LCA, retinitis pigmentosa (RP) is the diagnosis given to patients with photoreceptor degeneration who have good central vision within the first decade of life with subsequent progression of the disease until all useful vision is lost. Both disorders feature attenuated retinal vessels, varying amounts of pigmentary deposits, and a reduced or nondetectable ERG at all ages. There is no universal diagnosis for patients with retinal degeneration who lose useful vision during the first few years of life. These cases are diagnosed as either LCA or RP. The amount of disease overlap and lack of discriminating features between LCA and RP suggests that LCA may represent a severe form or extreme end of a group of heterogeneous retinal diseases named RP. In fact, mutations in one gene, RPE65, have been shown to cause both LCA and RP, supporting this view. We are using the candidate gene approach to identify genes responsible for inherited juvenile retinal degeneration such as LCA and early-onset RP. Mutation analysis will be performed using a high-throughput streamlined protocol designed to establish a genotype-phenotype correlation.
(b) The Function of TULP1 in Normal Photoreceptors and in Photoreceptor Degeneration. The objectives here are to explore the physiologic properties of the TULP1 gene product in the retina and define the underlying pathogenic mechanism responsible for photoreceptor degeneration associated with TULP1 mutations. Using a candidate gene approach, we identified mutations in TULP1 that cause a form of autosomal recessive retinitis pigmentosa (RP), a group of progressive retinal degenerations leading to blindness. TULP1 is a member of an evolutionarily conserved family of four proteins with unknown function named tubby-like proteins or TULPs. We identified four mutations in the coding region of TULP1 in two unrelated families diagnosed with RP. Subsequent reports have identified additional mutations in this gene to cause recessive RP. In mice, two members of the TULP family have been linked to neurosensory disorders including retinal degeneration, namely Tulp1 and Tubby. Loss of Tulp1 function, introduced by gene knockout, causes photoreceptor degeneration and a spontaneous recessive null mutation in the tubby gene causes photoreceptor and cochlear degeneration and adult-onset obesity. Tulp1 knockout mice exhibit an overlapping retinal phenotype with other mouse models whose gene targets have been shown to be involved in rhodopsin transport from the inner segments to the outer segments of photoreceptor cells. Our hypothesis is that TULP1 is involved in the transport of nascent opsin synthesized in the inner segment compartment to its final location in the outer segment compartment of photoreceptor cells.
Personnel: John S. Crabb, Jiayin Gu, Xiaorong Gu, Kwok Peng Ng, Renganathan Kutralanathan, Xianglin Yuan, Xiuzhen Yue and Xianquan Zhan
(c) Studies of Visual Cycle Proteins and their Role in Photoreceptor Degeneration CRALBP appears to play a fundamental role in vitamin A metabolism in the retina and retinal pigment epithelium (RPE). Mutations in the human CRALBP gene can result in retinal disease, detectable in children as early as ages 3 and 4. By establishing a molecular basis for understanding the normal structure, function and regulation of CRALBP, CRALBP-related visual disorders can be identified and therapies developed. The hypothesis of this proposal is that CRALBP plays a fundamental role in vitamin A metabolism in the retina and retinal pigment epithelium (RPE). Aims focus on both the CRALBP protein and gene. The unifying long-range research goals are to establish a molecular basis for understanding the normal structure, function and regulation of CRALBP in order that questions concerning CRALBP-related visual disorders can be answered.