The Hermansky-Pudlak syndrome (HPS) [MIM#203300] is an autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding tendency, and a ceroid-lipofuscin-like lysosomal storage disease. Frequent medical problems seen in HPS patients include eyesight problems (myopia, nystagmus, strabismus, and prolonged bleeding, progressive pulmonary fibrosis, and granulomatous (Witkop et al 1990 and Spritz et al 1998). There is no specific or effective treatment for HPS. Patient average survival is 30 to 50 years, death usually resulting from restrictive lung disease (68%), hemorrhage (17%), or colitis (15% (Witkop et al. 1990). HPS is a rare genetic condition worldwide. Nevertheless, HPS is thought to be the most common single-gene disorder on the island of Puerto Rico (PR), particularly in the northwestern region, where it has been reported to occur with an incidence of 1:1800 (Witkop et al, 1990), as well as a long-isolated mountain village in the Swiss Valais (Lattion et al, 1983 and Schallreuter et al. 1993) HPS is thus a significant public health problem in Puerto Rico. The laboratory of Dr. Richard A. Spritz, our consultant in this project, (Oh et al, 1996) mapped and cloned a gene responsible for HPS in both the PR and Swiss patients. The current proposal is aimed at identifying the genetic defect of a sector of the Puerto Rican HPS patient population at this high-risk population. We propose to investigate the molecular basis of HPS in Puerto Rican patients who lack the typical-16-HPS1 gene frameshift duplication. As will be discussed in the proposal, we expect that these patients may not have any mutation in the 10q23HPS1 gene, and thus will be useful for mapping a third, """"""""HPS3"""""""" locus. This will be bone by directed screening of target genes. We propose the following research strategy to approach our principal goal: systematic characterization of the genetic defect(s) causing HPS in Puerto Ricans. I. (a) Examine the HPS1 exon 15 duplication-negative PR patients for other mutations in the HPS1 gene. I. (b) Examine the platelet dense bodies in all HPS1 exon 15 duplication negative patients. II. Examine the HPS1 exon 15 duplication-negative PR patients for tyrosinase mutations to exclude OCAI plus an unusual bleeding disorder not related to HPS. III. Examine the Puerto Rican HPS1 exon 15 duplication-negative PR patients for mutations in the AP-3 adaptor complex subunits, as occurs in the mouse pearl mutant. IV. Determine the carrier frequency of the HPS1 exon 15 16 bp duplication mutation in the Puerto Rican population (both islandwide and in the Northwestern region of Puerto Rico) and eventually of other mutations that cause HPS. FUTURE DIRECTIONS: To map and eventually identify a third presumed HPS gene in the high-risk population of Puerto Rio by either identifying pathological mutations in the candidate genes proposed or by linkage disequilibrium analysis, which will form the basis for eventual isolation of the gene by positional cloning.
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