Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2

Pediatr Res. 2002 Feb;51(2):150-8. doi: 10.1203/00006450-200202000-00006.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 3
  • Adaptor Protein Complex beta Subunits
  • Adaptor Proteins, Vesicular Transport
  • Adult
  • Antigens, CD / metabolism
  • Blood Platelets / metabolism
  • Blood Platelets / ultrastructure
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Membrane / metabolism
  • Child, Preschool
  • Codon, Nonsense*
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Hermanski-Pudlak Syndrome / diagnosis
  • Hermanski-Pudlak Syndrome / genetics*
  • Hermanski-Pudlak Syndrome / pathology
  • Hermanski-Pudlak Syndrome / physiopathology
  • Humans
  • Inclusion Bodies / ultrastructure
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins*
  • Monomeric Clathrin Assembly Proteins*
  • Phenotype
  • Platelet Membrane Glycoproteins / metabolism
  • Protein Subunits
  • Proteins / chemistry
  • Proteins / genetics*
  • Proteins / metabolism
  • Tetraspanin 30


  • 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