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Published on: August 24, 2013
The zebrafish mutant lbk/vam6 resembles human multisystemic disorders caused by aberrant trafficking of endosomal
Helia B Schonthaler1, Valerie C Fleisch, Oliver Biehlmaier
1Swiss Federal Institute of Technology, Department of Biology, and Brain Research Institute of the University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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.
Insights
The zebrafish lbk mutant, lacking vam6/vps39 gene function, offers a new model for human diseases caused by defective vesicle transport. This model exhibits multiple organ defects and impaired vision, highlighting vam6
Area of Science:
- Cell Biology
- Genetics
- Developmental Biology
Background:
- Intracellular vesicle trafficking is crucial for cellular function and its disruption is linked to various human diseases.
- Defects in vesicle transport are implicated in conditions such as ARC syndrome, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Griscelli syndrome.
Purpose of the Study:
- To identify and characterize a novel zebrafish model for disorders associated with defective intracellular vesicle trafficking.
- To investigate the function of the vam6/vps39 gene in a multicellular organism and its role in cellular processes and disease pathogenesis.
Main Methods:
- Identification of the zebrafish mutant lbk.
- Positional cloning, allele screening, and morpholino knock-down to identify the causative gene mutation.
- Phenotypic analysis of affected tissues (melanocytes, RPE, liver, intestine, macrophages) and physiological/behavioral assessments.
Main Results:
- The lbk mutant displays hypopigmentation, absence of iridophore reflections, organ defects (liver, intestine), and impaired vision and innate immunity.
- Positional cloning revealed a mutation in the zebrafish vam6/vps39 gene, encoding a component of the HOPS complex essential for vesicle tethering and fusion.
- Affected cells exhibit enlarged intracellular vesicles, confirming a defect in vesicle trafficking.
Conclusions:
- The zebrafish lbk mutant is a valuable model for studying the physiological consequences of vam6/vps39 dysfunction in a multicellular organism.
- This study provides the first phenotypic description of vam6 gene loss in a vertebrate, linking it to a spectrum of cellular and organismal defects.
- The lbk model offers insights into human diseases characterized by defective vesicle transport and suggests vam6 as a potential disease gene.
