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Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene

Nature Genetics volume 30, pages 321324 (2002) | Download Citation



Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding and pulmonary fibrosis result from defects of melanosomes, platelet dense granules and lysosomes1,2,3,4. HPS is common in Puerto Rico5,6, where it is caused by mutations in the genes HPS17 and, less often, HPS3 (ref. 8). In contrast, only half of non–Puerto Rican individuals with HPS have mutations in HPS1 (ref. 9), and very few in HPS3 (ref. 10). In the mouse, more than 15 loci manifest mutant phenotypes similar to human HPS11,12, including pale ear (ep), the mouse homolog of HPS1 (refs 13,14). Mouse ep has a phenotype identical to another mutant, light ear (le)15,16,17,18, which suggests that the human homolog of le is a possible human HPS locus. We have identified and found mutations of the human le homolog, HPS4, in a number of non–Puerto Rican individuals with HPS, establishing HPS4 as an important HPS locus in humans. In addition to their identical phenotypes, le and ep mutant mice have identical abnormalities of melanosomes, and in transfected melanoma cells the HPS4 and HPS1 proteins partially co-localize in vesicles of the cell body. In addition, the HPS1 protein is absent in tissues of le mutant mice. These results suggest that the HPS4 and HPS1 proteins may function in the same pathway of organelle biogenesis.

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This work was supported by grants from the National Insitutes of Health (to R.A.S, R.T.S. and the Roswell Park Cancer Institute) and the Wellcome Trust (to E.V.S.). We thank A. Wilson, Y. Jiang, L. Zhen, D. Tabaczynski, D. Poslinski and M.K. Ellsworth for technical assistance.

Author information


  1. Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.

    • Tamio Suzuki
    •  & Richard A. Spritz
  2. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Wei Li
    • , Qing Zhang
    • , Amna Karim
    • , Edward K. Novak
    •  & Richard T. Swank
  3. Department of Anatomy and Cell Biology, St. George's Hospital Medical School, London, UK.

    • Elena V. Sviderskaya
    • , Simon P. Hill
    •  & Dorothy C. Bennett
  4. Departments of Ophthalmology, Pediatrics, and Genetics, Hospital for Sick Children, Toronto, Ontario, Canada.

    • Alex V. Levin
  5. Department of Hematology, University Hospital Utrecht, Utrecht, Netherlands.

    • H. Karel Nieuwenhuis
  6. Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA.

    • Chin-To Fong
  7. Genetische Beratungsstelle, Bolzano, Italy.

    • Claudio Castellan
  8. Abteilung für Molekulare Humangenetik, Ruhr-Universität Bochum, Bochum, Germany.

    • Bianca Miterski


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Correspondence to Richard A. Spritz.

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