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	Marjan Huizing, Charles D Scher, Erin Strovel, Diana L Fitzpatrick, Lisa M Hartnell, Yair Anikster, William A Gahl
Journal	Pediatric research (Pediatr Res) Vol. 51 Issue 2 Pg. 150-8 (Feb 2002) ISSN: 0031-3998 [Print] United States
PMID	11809908 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	AP3B1 protein, human Adaptor Protein Complex 3 Adaptor Protein Complex beta Subunits Adaptor Proteins, Vesicular Transport Antigens, CD CD63 protein, human Carrier Proteins Codon, Nonsense Membrane Proteins Membrane Transport Proteins Monomeric Clathrin Assembly Proteins Platelet Membrane Glycoproteins Protein Subunits Proteins Tetraspanin 30 clathrin assembly protein AP180
Topics	Adaptor Protein Complex 3 Adaptor Protein Complex beta Subunits Adaptor Proteins, Vesicular Transport Adult Antigens, CD (metabolism) Blood Platelets (metabolism, ultrastructure) Carrier Proteins (genetics, metabolism) Cell Membrane (metabolism) Child, Preschool Codon, Nonsense Female Fibroblasts (metabolism, pathology) Hermanski-Pudlak Syndrome (diagnosis, genetics, pathology, physiopathology) Humans Inclusion Bodies (ultrastructure) Male Membrane Proteins (genetics, metabolism) Membrane Transport Proteins Monomeric Clathrin Assembly Proteins Phenotype Platelet Membrane Glycoproteins (metabolism) Protein Subunits Proteins (chemistry, genetics, metabolism) Tetraspanin 30

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