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J Med Genet 46:803-810 doi:10.1136/jmg.2008.065961
  • Original article

Clinical and cellular characterisation of Hermansky–Pudlak syndrome type 6

  1. M Huizing1,
  2. B Pederson1,
  3. R A Hess1,
  4. A Griffin1,
  5. A Helip-Wooley1,
  6. W Westbroek1,
  7. H Dorward1,
  8. K J O’Brien1,2,
  9. G Golas1,2,
  10. E Tsilou3,
  11. J G White4,
  12. W A Gahl1,2
  1. 1
    Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  2. 2
    Office of Rare Diseases, Intramural Program, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA
  3. 3
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA
  4. 4
    Department of Laboratory Medicine, University of Minnesota, Minneapolis, Minnesota, USA
  1. Correspondence to Dr M Huizing, Medical Genetics Branch, NHGRI, NIH, 10 Center Drive, MSC 1851, Building 10, Room 10C-103, Bethesda, Maryland 20892-1851, USA; mhuizing{at}mail.nih.gov
  • Received 31 December 2008
  • Revised 16 April 2009
  • Accepted 23 April 2009
  • Published Online First 20 October 2009

Abstract

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.

Footnotes

  • Additional figure and table are published online only at http://jmg.bmj.com/content/vol46/issue12

  • Funding This work was supported by the Intramural Research programs of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.