The aim of this project is to clone and characterize the gene for a form of syndromic retinitis pigmentosa (RP), called. Hallervorden-Spatz syndrome (HSS) and characterized by abnormal electroretinogram, lipofuscin accumulation in the retinal pigment epithelium, and pigmentary retinopathy. Other features include dystonia, due to massive iron accumulation in the basal ganglia, and progressive deterioration leading to early death. Though lipid peroxidation is an hypothesized mechanism leading to the HSS phenotype, no knowledge exists of the molecular or biochemical defect in HSS. We have a unique opportunity to map the HSS gene using linkage analysis (homozygosity mapping) in a consanguineous Amish family with multiple affected members. Once the HSS gene has been mapped, we will search for mutations in candidate genes, as well as identify novel transcribed sequences that may contain the HSS gene. We will then characterize the gene and its protein product through homology studies to known sequences. Knowledge of the molecular basis of this disease will lead to a better understanding of the pathophysiologic process causing its pleiotropic effects. Understanding the etiology of a rare disease will often illuminate the mechanism at work in common, related diseases. Furthermore, by studying syndromic RP, we can use information about all of the syndrome manifestations (e.g. patterns of tissue expression, common metabolic or developmental pathways) to theorize a disease mechanism. Inference of a pathophysiologic process from a defective gene has proved frustrating for the forms of RP that are due to mutation in retina-specific genes. The HSS gene is not retina-specific, and a defect in it must account for rod photoreceptor degeneration as well as regional brain iron accumulation. Once the HSS gene is cloned and characterized, the other pathologic changes may provide a context for understanding the mechanism of pigmentary retinopathy. Since defects in this non-retina-specific process may cause other forms of syndromic and isolated RP and may be integral in disorders of lipofuscin accumulation, including aging macular degeneration, identification of the HSS gene may lead to greater understanding of RP as well as the macular dystrophies associated with sene ence. The HSS project forms the research core of Dr. Hayflick's training to become an independent biomedical investigator. Dr. Michael Litt, internationally recognized in the field of genetics, will he her primary sponsor with Dr. Richard Weleber, accomplished in the study of hereditary retinal diseases, as secondary sponsor. Unique strengths of her training program include a period of intense study in the Visiting Investigator Program through the National Center for Human Genome Research, which will provide her with expertise that will complement but not duplicate existing University research strengths, and the Oregon Health Sciences University and Department of Molecular and Medical Genetics research environments, which effectively foster collaboration with a diverse group of outstanding investigators.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Physician Scientist Award (K11)
Project #
5K11EY000348-03
Application #
2459047
Study Section
Vision Research and Training Committee (VSN)
Project Start
1995-08-01
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Genetics
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Taylor, T D; Litt, M; Kramer, P et al. (1996) Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. Nat Genet 14:479-81