Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency

Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, display s extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and AD TB3A mutations cause HPS-2 disease, which is known to involve abnormal intr acellular vesicle formation. A third HPS-causing gene, HPS3, was recently i dentified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characte ristics of eight patients with HPS-3 who are of non-Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G -->A s plice-site mutation that causes skipping of exon 5, deleting an RsaI restri ction site and decreasing the amounts of mRNA found on northern blotting. T he other two are heterozygous for the 1303+1G -->A mutation and for either an 1831+2T -->G or a 2621-2A -->G splicing mutation. Of 235 anonymous Ashke nazi Jewish DNA samples, one was heterozygous for the 1303+1G -->A mutation . One seven-year-old boy of German/Swiss extraction was compound heterozygo us for a 2729+1G -->C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is norma l in amount but is increased in size. A 12-year-old girl of Puerto Rican an d Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewis h patients had received the diagnosis of ocular, rather than oculocutaneous , albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS.