RT Journal Article
SR Electronic
T1 Clinical and cellular characterisation of Hermansky–Pudlak syndrome type 6
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 803
OP 810
DO 10.1136/jmg.2008.065961
VO 46
IS 12
A1 M Huizing
A1 B Pederson
A1 R A Hess
A1 A Griffin
A1 A Helip-Wooley
A1 W Westbroek
A1 H Dorward
A1 K J O’Brien
A1 G Golas
A1 E Tsilou
A1 J G White
A1 W A Gahl
YR 2009
UL http://jmg.bmj.com/content/46/12/803.abstract
AB Background: 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.Aim: To characterise extensively 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 genomic region. 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: The HPS-6 subtype resembles other BLOC-2 defective subtypes (that is, 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.