Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor

Mol Cell. 1999 Jan;3(1):11-21. doi: 10.1016/s1097-2765(00)80170-7.


Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defective lysosome-related organelles. Here, we report the identification of two HPS patients with mutations in the beta 3A subunit of the heterotetrameric AP-3 complex. The patients' fibroblasts exhibit drastically reduced levels of AP-3 due to enhanced degradation of mutant beta 3A. The AP-3 deficiency results in increased surface expression of the lysosomal membrane proteins CD63, lamp-1, and lamp-2, but not of nonlysosomal proteins. These differential effects are consistent with the preferential interaction of the AP-3 mu 3A subunit with tyrosine-based signals involved in lysosomal targeting. Our results suggest that AP-3 functions in protein sorting to lysosomes and provide an example of a human disease in which altered trafficking of integral membrane proteins is due to mutations in a component of the sorting machinery.

MeSH terms

  • Adaptor Proteins, Vesicular Transport
  • Albinism, Oculocutaneous / genetics*
  • Antigens, CD / metabolism
  • DNA Mutational Analysis
  • Fibroblasts
  • Flow Cytometry
  • Humans
  • Lysosome-Associated Membrane Glycoproteins
  • Melanosomes / metabolism
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Monomeric Clathrin Assembly Proteins*
  • Nerve Tissue Proteins / genetics*
  • Phosphoproteins / genetics*
  • Platelet Membrane Glycoproteins / metabolism
  • Protein Processing, Post-Translational / genetics
  • Proteins / metabolism*
  • RNA, Messenger / metabolism
  • Tetraspanin 30


  • Adaptor Proteins, Vesicular Transport
  • Antigens, CD
  • CD63 protein, human
  • HPS1 protein, human
  • Lysosome-Associated Membrane Glycoproteins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Monomeric Clathrin Assembly Proteins
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Platelet Membrane Glycoproteins
  • Proteins
  • RNA, Messenger
  • Tetraspanin 30
  • clathrin assembly protein AP180
  • lysosomal proteins

Associated data

  • GENBANK/AF092092