Nature Genetics
28, 376 - 380 (2001)
Published online: 16 July 2001; | doi:10.1038/ng576
Mutation of a new gene causes a unique form of Hermansky−Pudlak syndrome in a genetic isolate of central Puerto RicoYair Anikster1, Marjan Huizing1, James White2, Yuriy O. Shevchenko3, Diana L. Fitzpatrick1, Jeffrey W. Touchman3, John G. Compton4, Sherri J. Bale4, Richard T. Swank5, William A. Gahl1
& Jorge R. Toro4, 61
Section on Human Biochemical Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA. 2
Department of Laboratory Medicine, University of Minnesota, Minneapolis, Minnesota, USA. 3
National Institutes of Health Intramural Sequencing Center, National Institutes of Health, Gaithersburg, Maryland, USA. 4
Genetic Studies Section, Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. 5
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA. 6
National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Correspondence should be addressed to William A. Gahl bgahl@helix.nih.govHermansky−Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a storage pool deficiency due to an absence of platelet dense bodies1,
2,
3. Lysosomal ceroid lipofuscinosis, pulmonary fibrosis and granulomatous colitis are occasional manifestations of the disease4. HPS occurs with a frequency of one in 1,800 in north-west Puerto Rico5 due to a founder effect6. Several non-Puerto Rican patients also have mutations in HPS1
7,
8, which produces a protein of unknown function9. Another gene, ADTB3A, causes HPS in the pearl mouse10 and in two brothers with HPS-2 (refs. 11,12). ADTB3A encodes a coat protein involved in vesicle formation3,
13, implicating HPS as a disorder of membrane trafficking. We sought to identify other HPS-causing genes7,
8,
14. Using homozygosity mapping on pooled DNA of 6 families from central Puerto Rico, we localized a new HPS susceptibility gene to a 1.6-cM interval on chromosome 3q24. The gene, HPS3, has 17 exons, and a putative 113.7-kD product expected to reveal how new vesicles form in specialized cells. The homozygous, disease-causing mutation is a large deletion and represents the second example of a founder mutation causing HPS on the small island of Puerto Rico. We also present an allele-specific assay for diagnosing individuals heterozygous or homozygous for this mutation.
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