Abstract 804 Genetic Basis of Disease 1 Platform, Monday, 5/3

HPS consists of oculocutaneous albinism, a platelet storage-pool deficiency, and ceroid lipofuscinosis. Patients exhibit congenital nystagmus, iris transillumination, impaired visual acuity, hypopigmentation, and a bleeding diathesis. Some individuals have granulomatous colitis, and a progressive, fatal pulmonary fibrosis develops in the fourth or fifth decade. The disorder is common in northwest Puerto Rico, but occurs throughout the world. HPS-1, a gene on chromosome 10q23 known to cause HPS, codes for a 79.3 kD protein of unknown function. Patients from northwest Puerto Rico are homozygous for a 16-bp duplication in exon 15 of HPS-1. The basic defect in HPS is unknown, but 14 mouse models exist with hypopigmentation and a storage pool deficiency.

We investigated 80 Puerto Rican and non-Puerto Rican HPS patients at the NIH Clinical Center. Patients with the 16-bp duplication were at increased risk for pulmonary fibrosis. Patients from Central Puerto Rico had entirely normal HPS-1 genes and exhibited milder hypopigmentation compared with duplication patients. Their genetic defect is being mapped by linkage analysis. Among our 27 non-Puerto Rican patients, only 5 have mutations in HPS-1; one of these died of pulmonary fibrosis at age 37. Twenty individuals have HPS due to a gene not yet identified, and two brothers have mutations in the beta-3A subunit of adaptor complex-3 (AP-3). This heterotetrameric coat protein facilitates the formation of vesicles from donor membranes. The brothers represent the first humans identified with a mutation in a coat protein involved in vesicle trafficking. The various genes which cause HPS appear to comprise a pathway responsible for the genesis of melanosomes, platelet dense bodies, and lysosomes.