Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6

Abstract

Purpose In the last decade, Hermansky-Pudlak syndrome (HPS) has arisen as an instructive disorder for cell biologists to study the biogenesis of lysosome-related organelles (LROs). Of the eight human HPS subtypes, only subtypes 1 through 5 are well described. Here, we carefully characterize the HPS-6 subtype, caused by defects in HPS6, a subunit of the biogenesis of lysosome-related organelles complex-2 (BLOC-2). Methods Mutation analysis for the HPS6 gene was performed on DNA from our group of unclassified HPS patients. The clinical phenotype of patients with HPS6 mutations was then carefully ascertained, and their cultured dermal melanocytes were employed for cellular immunofluorescence studies. Results Molecular studies showed a variety of mutations in the single-exon HPS6 gene, including frame shift, missense, and nonsense mutations as well as a ~20-kb deletion spanning the entire HPS6 gene. Cellular studies revealed that the melanogenic proteins tyrosinase and tyrosinase-related protein 1 failed to be efficiently delivered to the melanosomes of HPS-6 patients, explaining their hypopigmentation. Clinical studies indicated that HPS-6 patients exhibit oculocutaneous albinism and a bleeding diathesis. Importantly, granulomatous colitis and pulmonary fibrosis, debilitating features present in HPS subtypes 1 and 4, were not detected in our HPS-6 patients. Conclusion In sum, the HPS-6 subtype resembles other BLOC-2 defective subtypes (i.e., HPS-3 and HPS-5) in its molecular, cellular and clinical findings. These findings are not only important for providing a prognosis to newly diagnosed HPS-6 patients, but also for further elucidation of HPS function in the biogenesis of LROs.

BLOC-2, AP-3, and AP-1 Proteins Function in Concert with Rab38 and Rab32 Proteins to Mediate Protein Trafficking to Lysosome-related Organelles

“…7 and 8A). Thus, Rab32 appears to more clearly cooperate with Rab38 in pathways utilized by cargo such as tyrosinase and Tyrp1, which are also known to depend on AP-3, AP-1, and BLOC-2 (4,11,14,15,17,18,20,47,48,51). Interestingly, the trafficking of Tyrp2 has been far less characterized compared with that of tyrosinase and Tyrp1.…”

Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome

“…6,7 These mice offer an opportunity to explore the contribution of granules during thrombus formation. Among the contents of platelet dense granules, polyphosphates have been proposed as activators through factor XII or factor V on platelet stimulation and polyphosphate secretion.…”

The Management of Gastrointestinal Disease in Hermansky-Pudlak Syndrome

“…In HPS, an error in lysosomal vesicle production creates an accumulation of ceroid in the macrophages. 7,18 The accumulation of ceroid eventually leads to a fatal rupture of the macrophages, which initiates a robust inflammatory response. The cytokine response of inflammation increases levels of tumor necrosis factor-a.…”