EVIDENCE FOR LOCUS HETEROGENEITY IN PUERTO-RICANS WITH HERMANSKY-PUDLAK-SYNDROME

Hermansky-Pudlak syndrome (HPS) consists of oculocutaneous albinism, a platelet storage-pool deficiency, and ceroid lipofuscinosis. In a rec ent report on the cloning of an HPS gene, all 22 Puerto Rican HPS pati ents were homozygous for a 16-bp duplication in exon 15. This presumab ly reflected a founder effect for the HPS mutation in Puerto Rico. Nev ertheless, we ascertained two individuals from central Puerto Rico who lacked the 16-bp duplication, exhibited significant amounts of normal -size HPS mRNA by northern blot analysis, and had haplotypes in the HP S region that were different from the haplotype of every 16-bp-duplica tion patient. Moreover, these two individuals displayed no mutations i n their cDNA sequences, throughout the entire HPS gene. Both patients exhibited pigment dilution, impaired visual acuity, nystagmus, a bleed ing diathesis, and absent platelet dense bodies, confirming the diagno sis of HPS. These findings indicate that analysis of Puerto Rican pati ents for the 16-bp duplication in HPS cannot exclude the diagnosis of HPS. In addition, HPS most likely displays locus heterogeneity, consis tent with the existence of several mouse strains manifesting both pigm ent dilution and a platelet storage-pool deficiency.