letter 376 nature genetics • volume 28 • august 2001 Hermansky–Pudlak syndrome (HPS) is a rare autosomal reces- sive disorder characterized by oculocutaneous albinism and a storage pool deficiency due to an absence of platelet dense bodies 1–3 . Lysosomal ceroid lipofuscinosis, pulmonary fibrosis and granulomatous colitis are occasional manifestations of the disease 4 . HPS occurs witha frequency of one in 1800 in north- west Puerto Rico 5 due to a founder effect 6 . Several non-Puerto Rican patients also have mutations in HPS1 7,8 , w hich produces a protein of unknow n function 9 . Another gene, ADTB3A, causes HPS in the pearl mouse 10 and in two brothers with HPS-2 (refs. 11,12). ADTB3A encodes a coat protein involved in vesicle for- mation 3,13 , implicating HPS as a disorder of membrane traf- ficking. We sought to identify other HPS-causing genes 7,8,14 . Using homozygosity mapping on pooled DNA of 6 families from central Puerto Rico, we localized a new HPS susceptibil- ity 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 secon example of a founder muta- tion causing HPS on the small island of Puerto Rico. We also present an allele-specific assay for diagnosing individu- als heterozygous or homozy- gous for this mutation. In studying Puerto Rican families with HPS, we evalu- ated the possible existence of a genetic isolate of the disease in central Puerto Rico 13 by exam- ining six families (Fig. 1a) from Aibonito, Naranjito and Bar- ranquitas, rural towns south of San Juan (Fig. 1b). We identi- fied the 13 affected individuals available to us based upon their medical histories and clinical findings, including a bleeding diathesis, horizontal nystag- mus, decreased vision and very mild pigment dilution of hair, skin and irides (Fig. 1c ). We confirmed the diagnosis of HPS by demonstrating an absence of platelet dense bodies using wet-mount electron microscopy 14,15 (Fig. 1c ). All patients lacked the 16-bp duplication in HPS1 (ref. 6). Fig. 1 HPS in central Puerto Rico. a, Pedigrees of central Puerto Rican HPS families used for mapping. b, Map show- ing the region of north west Puerto Rico where HPS-1 is prevalent and the area of central Puerto Rico where the new genetic isolate of HPS-3 was found. c, Hair, skin and eye pigmentation (top panels), iris transillumination (mid- dle panels) and wet-mount electron microscopy of platelets (bottom panels) in a non-HPS albino (left) and a member of the central Puerto Rican HPS population (patient E-II-1, patient #2 of ref. 14). Note the mild degree of skin and hair hypopigmentation in the HPS patient and her minimal iris transillumination compared with the classical albino patient. (Iris transillumination is the appearance of light, shone through the pupil, in the iris because there is insuffi- cient iris pigment to block transmission.) A normal contin- gent of dense bodies appears in the platelets of the non-HPS albino patient, whereas the HPS platelets lack dense bodies entirely. M utation of a new gene causes a unique form of Hermansky–Pudlak syndrome in a genetic isolate of central Puerto Rico Yair Anikster 1 , Marjan Huizing 1 , James White 2 , Yuriy O. Shevchenko 3 , Diana L. Fitzpatrick 1 , Jeffrey W. Touchman 3 , John G. Compton 4 , Sherri J. Bale 4 , Richard T. Swank 5 , William A. Gahl 1 & Jorge R. Toro 4,6 1 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: W.A.G. (e-mail: bgahl@helix.nih.gov). Published online: 16 July 2001, DOI: 10.1038/ng576 a b c © 2001 Nature Publishing Group http://genetics.nature.com © 2001 Nature Publishing Group http://genetics.nature.com