title: Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency.
abstract: Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and ADTB3A mutations cause HPS-2 disease, which is known to involve abnormal intracellular vesicle formation. A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characteristics of eight patients with HPS-3 who are of non-Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G-->A splice-site mutation that causes skipping of exon 5, deleting an RsaI restriction site and decreasing the amounts of mRNA found on northern blotting. The other two are heterozygous for the 1303+1G-->A mutation and for either an 1831+2T-->G or a 2621-2A-->G splicing mutation. Of 235 anonymous Ashkenazi Jewish DNA samples, one was heterozygous for the 1303+1G-->A mutation. One seven-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G-->C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is normal in amount but is increased in size. A 12-year-old girl of Puerto Rican and Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS.
authors.affiliation: Section on Human Biochemical Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: M
authors.initials: M
authors.lastname: Huizing
authors.forename: Y
authors.initials: Y
authors.lastname: Anikster
authors.forename: D L
authors.initials: DL
authors.lastname: Fitzpatrick
authors.forename: A B
authors.initials: AB
authors.lastname: Jeong
authors.forename: M
authors.initials: M
authors.lastname: D'Souza
authors.forename: M
authors.initials: M
authors.lastname: Rausche
authors.forename: J R
authors.initials: JR
authors.lastname: Toro
authors.forename: M I
authors.initials: MI
authors.lastname: Kaiser-Kupfer
authors.forename: J G
authors.initials: JG
authors.lastname: White
authors.forename: W A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D016115:Albinism, Oculocutaneous / Q000235:genetics / Q000503:physiopathology; D017398:Alternative Splicing / Q000235:genetics; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D018703:Founder Effect; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D017496:Hypopigmentation / Q000235:genetics* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns / Q000235:genetics; D007585:Jews / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010981:Platelet Storage Pool Deficiency / Q000235:genetics* / Q000503:physiopathology; D011506:Proteins / Q000235:genetics; D011647:Puerto Rico; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics
chemical_list: C439973:AP3B1 protein, human; D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D002352:Carrier Proteins; C102160:HPS1 protein, human; C432680:HPS3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D011506:Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger