Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico.
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.
Anikster
Y
Y
Section on Human Biochemical Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Huizing
M
M
White
J
J
Shevchenko
Y O
YO
Fitzpatrick
D L
DL
Touchman
J W
JW
Compton
J G
JG
Bale
S J
SJ
Swank
R T
RT
Gahl
W A
WA
Toro
J R
JR
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
D002352:Carrier Proteins; C432680:HPS3 protein, human; D047908:Intracellular Signaling Peptides and Proteins