Abstract
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
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Adaptor Proteins, Vesicular Transport
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Albinism, Oculocutaneous / genetics*
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Antigens, CD / metabolism
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DNA Mutational Analysis
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Fibroblasts
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Flow Cytometry
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Humans
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Lysosomal Membrane Proteins
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Melanosomes / metabolism
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Membrane Glycoproteins / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Microscopy, Fluorescence
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Molecular Sequence Data
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Monomeric Clathrin Assembly Proteins*
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Nerve Tissue Proteins / genetics*
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Phosphoproteins / genetics*
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Platelet Membrane Glycoproteins / metabolism
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Protein Processing, Post-Translational / genetics
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Proteins / metabolism*
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RNA, Messenger / metabolism
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Tetraspanin 30
Substances
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Adaptor Proteins, Vesicular Transport
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Antigens, CD
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CD63 protein, human
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HPS1 protein, human
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Lysosomal Membrane Proteins
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Membrane Glycoproteins
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Membrane Proteins
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Monomeric Clathrin Assembly Proteins
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Nerve Tissue Proteins
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Phosphoproteins
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Platelet Membrane Glycoproteins
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Proteins
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RNA, Messenger
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Tetraspanin 30
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clathrin assembly protein AP180
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lysosomal proteins