Mutation of a new gene causes a unique form of Hermansky–Pudlak syndrome in a genetic isolate of central Puerto Rico

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Hermansky–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 HPS17,8, 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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Figure 1: HPS in central Puerto Rico.
Figure 2: Homozygosity mapping of HPS-3.
Figure 3: Northern-blot analyses using a probe to a portion of HPS3 cDNA.
Figure 4: Structure of the HPS3 deletion and multiplex PCR amplification assay for its presence or absence.
Figure 5: Amino acid sequence of the HPS3 protein, consisting of 1,004 amino acids.

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Y. Anikster is a Howard Hughes Medical Institute Physician Postdoctoral Fellow. The authors thank J.Sanchez, Chairman, Department of Dermatology, University of Puerto Rico-Medical Sciences Campus, for his helpful assistance, J.L. Arribas for his genealogical information and C.N. Rodriguez for serving as patient liaison. The authors appreciate the advice of R. King of the University of Minnesota, the consultation of R. Kleta and the excellent technical assistance of I. Bernardini. Supported in part by grant HL31698 (RTS) and by the Roswell Park Cancer Institute Cancer Center Support Grant CA16506.

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Correspondence to William A. Gahl.

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