The zebrafish mutant lbk/vam6 resembles human multi-systemic disorders caused by aberrant trafficking of endosomal vesicles

Schonthaler, H.B., Fleisch, V.C., Biehlmaier, O., Makhankov, Y., Rinner, O., Bahadori, R., Geisler, R., Schwarz, H., Neuhauss, S.C., and Dahm, R.
Development (Cambridge, England)   135(2): 387-399 (Journal)
Registered Authors
Bahadori, Ronja, Biehlmaier, Oliver, Dahm, Ralf, Fleisch, Valerie, Geisler, Robert, Neuhauss, Stephan, Rinner, Oliver
Zebrafish development, Eye, Vision, Pigmentation, Liver, Vesicle trafficking, Lysosomes and lysosome-related organelles, Vam6p/Vps39
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Biological Transport/drug effects
  • Chromosome Mapping
  • Endosomes/drug effects
  • Endosomes/metabolism*
  • Endosomes/pathology*
  • Gastrointestinal Tract/drug effects
  • Gastrointestinal Tract/pathology
  • Gastrointestinal Tract/ultrastructure
  • Hepatomegaly/pathology
  • Humans
  • Immunity, Innate/drug effects
  • Intracellular Signaling Peptides and Proteins/chemistry
  • Intracellular Signaling Peptides and Proteins/genetics
  • Intracellular Signaling Peptides and Proteins/metabolism*
  • Larva/drug effects
  • Larva/microbiology
  • Liver/drug effects
  • Liver/pathology
  • Liver/ultrastructure
  • Molecular Sequence Data
  • Multiple System Atrophy/pathology*
  • Mutation/genetics*
  • Oligonucleotides, Antisense/pharmacology
  • Phenotype
  • Pigment Epithelium of Eye/drug effects
  • Pigment Epithelium of Eye/pathology
  • Pigment Epithelium of Eye/ultrastructure
  • Pigmentation/drug effects
  • Transport Vesicles/drug effects
  • Transport Vesicles/metabolism*
  • Vesicular Transport Proteins/chemistry
  • Vesicular Transport Proteins/genetics
  • Vesicular Transport Proteins/metabolism*
  • Vision, Ocular/drug effects
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/immunology
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
18077594 Full text @ Development
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes