title: The zebrafish mutant lbk/vam6 resembles human multisystemic disorders caused by aberrant trafficking of endosomal vesicles.
abstract: The trafficking of intracellular vesicles is essential for a number of cellular processes and defects in this process have been implicated in a wide range of human diseases. We identify the zebrafish mutant lbk as a novel model for such disorders. lbk displays hypopigmentation of skin melanocytes and the retinal pigment epithelium (RPE), an absence of iridophore reflections, defects in internal organs (liver, intestine) as well as functional defects in vision and the innate immune system (macrophages). Positional cloning, an allele screen, rescue experiments and morpholino knock-down reveal a mutation in the zebrafish orthologue of the vam6/vps39 gene. Vam6p is part of the HOPS complex, which is essential for vesicle tethering and fusion. Affected cells in the lbk RPE, liver, intestine and macrophages display increased numbers and enlarged intracellular vesicles. Physiological and behavioural analyses reveal severe defects in visual ability in lbk mutants. The present study provides the first phenotypic description of a lack of vam6 gene function in a multicellular organism. lbk shares many of the characteristics of human diseases and suggests a novel disease gene for pathologies associated with defective vesicle transport, including the arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, the Hermansky-Pudlak syndrome, the Chediak-Higashi syndrome and the Griscelli syndrome.
authors: Swiss Federal Institute of Technology, Department of Biology, and Brain Research Institute of the University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors: Helia B
authors: HB
authors: Schonthaler
authors: Valerie C
authors: VC
authors: Fleisch
authors: Oliver
authors: O
authors: Biehlmaier
authors: Yuri
authors: Y
authors: Makhankov
authors: Oliver
authors: O
authors: Rinner
authors: Ronja
authors: R
authors: Bahadori
authors: Robert
authors: R
authors: Geisler
authors: Heinz
authors: H
authors: Schwarz
authors: Stephan C F
authors: SC
authors: Neuhauss
authors: Ralf
authors: R
authors: Dahm
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002874:Chromosome Mapping; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006529:Hepatomegaly / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007814:Larva / Q000187:drug effects / Q000382:microbiology; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008969:Molecular Sequence Data; D019578:Multiple System Atrophy / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D010857:Pigment Epithelium of Eye / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D010858:Pigmentation / Q000187:drug effects; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014785:Vision, Ocular / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000276:immunology; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D033921:Vesicular Transport Proteins; D029961:Zebrafish Proteins; C526886:vps39 vacuolar protein sorting 39, Danio rerio