title: Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2.
abstract: Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disease consisting of oculocutaneous albinism and a storage pool deficiency resulting from absent platelet dense bodies. The disorder is genetically heterogeneous. The majority of patients, including members of a large genetic isolate in northwest Puerto Rico, have mutations in HPS1. Another gene, ADTB3A, was shown to cause HPS-2 in two brothers having compound heterozygous mutations that allowed for residual production of the gene product, the beta3A subunit of adaptor complex-3 (AP-3). This heterotetrameric complex serves as a coat protein-mediating formation of intracellular vesicles, e.g. the melanosome and platelet dense body, from membranes of the trans-Golgi network. We determined the genomic organization of the human ADTB3A gene, with intron/exon boundaries, and describe a third patient with beta3A deficiency. This 5-y-old boy has two nonsense mutations, C1578T (R-->X) and G2028T (E-->X), which produce no ADTB3A mRNA and no beta3A protein. The associated mu3 subunit of AP-3 is also entirely absent. In fibroblasts, the cell biologic concomitant of this deficiency is robust and aberrant trafficking through the plasma membrane of LAMP-3, an integral lysosomal membrane protein normally carried directly to the lysosome. The clinical concomitant is a severe, G-CSF-responsive neutropenia in addition to oculocutaneous albinism and platelet storage pool deficiency. Our findings expand the molecular, cellular, and clinical spectrum of HPS-2 and call for an increased index of suspicion for this diagnosis among patients with features of albinism, bleeding, and neutropenia.
authors.affiliation: Section on Human Biochemical Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Charles D
authors.initials: CD
authors.lastname: Scher
authors.forename: Erin
authors.initials: E
authors.lastname: Strovel
authors.forename: Diana L
authors.initials: DL
authors.lastname: Fitzpatrick
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hartnell
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D033942:Adaptor Proteins, Vesicular Transport; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism / Q000648:ultrastructure; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002675:Child, Preschool; D018389:Codon, Nonsense; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D022861:Hermanski-Pudlak Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins; D034041:Monomeric Clathrin Assembly Proteins; D010641:Phenotype; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D021122:Protein Subunits; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D060149:Tetraspanin 30
chemical_list: C439973:AP3B1 protein, human; D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; C554586:CD63 protein, human; D002352:Carrier Proteins; D018389:Codon, Nonsense; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D034041:Monomeric Clathrin Assembly Proteins; D010980:Platelet Membrane Glycoproteins; D021122:Protein Subunits; D011506:Proteins; D060149:Tetraspanin 30; C439023:clathrin assembly protein AP180