Cellular, Molecular and Clinical Characterization of Patients with Hermansky–Pudlak Syndrome Type 5

Hermansky–Pudlak syndrome (HPS) is a disorder of lysosome‐related organelles such as melanosomes and platelet dense granules. Seven genes are now associated with HPS in humans. An accurate diagnosis of each HPS subtype has important prognostic and treatment implications. Here we describe the cellular, molecular, and clinical aspects of the recently identified HPS‐5 subtype. We first analyzed the genomic organization and the RNA expression pattern of HPS5, located on chromosome 11p14, and demonstrated tissue‐specific expression of at least three alternatively spliced HPS5 mRNA transcripts, coding for HPS5A and HPS5B proteins, that differ at their 5′‐ends. Genetic screening of 15 unassigned HPS patients yielded six new HPS5 mutations in four patients. Clinically, our HPS‐5 patients exhibited iris transillumination, variable hair and skin pigmentation, and absent platelet dense bodies, but not pulmonary fibrosis or granulomatous colitis. In two patients with homozygous missense mutations, hemizygosity was ruled out by gene‐dosage multiplex polymerase chain reaction, and immunocytochemical analyses of their fibroblasts supported the HPS‐5 diagnosis. Specifically, LAMP‐3 distribution was restricted to the perinuclear region in HPS‐5 fibroblasts, in contrast to the normal LAMP‐3 distribution, which extended to the periphery. This specific intracellular vesicle distribution in fibroblasts, in combination with the clinical features, will improve the characterization of the HPS‐5 subtype.