title: Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico.
abstract: 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 bodies. Lysosomal ceroid lipofuscinosis, pulmonary fibrosis and granulomatous colitis are occasional manifestations of the disease. HPS occurs with a frequency of one in 1800 in north-west Puerto Rico due to a founder effect. Several non-Puerto Rican patients also have mutations in HPS1, which produces a protein of unknown function. Another gene, ADTB3A, causes HPS in the pearl mouse and in two brothers with HPS-2 (refs. 11,12). ADTB3A encodes a coat protein involved in vesicle formation, implicating HPS as a disorder of membrane trafficking. We sought to identify other HPS-causing genes. 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.
authors.affiliation: Section on Human Biochemical Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Anikster
authors.forename: M
authors.initials: M
authors.lastname: Huizing
authors.forename: J
authors.initials: J
authors.lastname: White
authors.forename: Y O
authors.initials: YO
authors.lastname: Shevchenko
authors.forename: D L
authors.initials: DL
authors.lastname: Fitzpatrick
authors.forename: J W
authors.initials: JW
authors.lastname: Touchman
authors.forename: J G
authors.initials: JG
authors.lastname: Compton
authors.forename: S J
authors.initials: SJ
authors.lastname: Bale
authors.forename: R T
authors.initials: RT
authors.lastname: Swank
authors.forename: W A
authors.initials: WA
authors.lastname: Gahl
authors.forename: J R
authors.initials: JR
authors.lastname: Toro
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D005838:Genotype; D022861:Hermanski-Pudlak Syndrome / Q000453:epidemiology / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009928:Organ Specificity; D010375:Pedigree; D010641:Phenotype; D020161:Physical Chromosome Mapping; D011647:Puerto Rico / Q000453:epidemiology; D017384:Sequence Deletion
chemical_list: D002352:Carrier Proteins; C432680:HPS3 protein, human; D047908:Intracellular Signaling Peptides and Proteins