| Abstract No.: | A-A1014 |
| Country: | Canada |
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| Title: | VALIDATION IN ZEBRAFISH OF A NOVEL MUTATION IN HUMAN AP1S1 CAUSING EKV3 SYNDROME |
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| Authors/Affiliations: | 1 Edna Brustein*; 2 Alexandre Montpetit; 1 Stéphanie Côté; 3 Christian A. Drouin; 1 Line Lapointe; 2 Michèle Boudreau; 1 Caroline Meloche; 4 Régen Drouin; 5 Thomas J. Hudson; 1 Patrick Cossette
1 University of Montreal, QC, Canada; 2 McGill University, Montreal, QC, Canada; 3 Grand-Portage Hospital, Rivière-du-Loup, QC, Canada; 4 Université de Sherbrooke, QC, Canada; 5 Ontario Institute for Cancer Research, Toronto, ON, Canada
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| Content: | Adaptor protein (AP) complexes regulate clathrin-coated vesicle assembly, protein cargo sorting and vesicular trafficking between organelles in eukaryotic cells. Because disruption of the various subunits of the AP complexes is embryonic lethal in the majority of cases, detailed characterization of their function in vivo is still lacking. We describe here the first mutation in the human AP1S1 gene, encoding the small subunit σ1A of the AP-1 complex. This splice mutation, which leads to a premature stop codon, was found in four families with Erythrokeratodermia Variabilis type 3 (EKV3) sharing a common ancestor from the Bas-St-Laurent region in the province of Quebec, Canada. EKV3 is characterized by various ichthyosiform skin lesions, psychomotor retardation, polyneuropathy, sensorineural hearing loss and chronic congenital diarrhea. To confirm the effect of the mutation and to better understand the in vivo function of AP1S1, we knocked down its expression in zebrafish. In this model, Ap1s1 knockdown resulted in a perturbation of epithelial cell polarity, a loss in pigmentation and in severe motility deficits, due to impaired neural network development and a major loss of interneurons. These morphological and behavioral phenotypes were rescued by co-injection with the wild-type human AP1S1 mRNA, but not by co-injecting the truncated form of AP1S1, suggesting a loss-of-function effect of this mutation. Together these results confirm AP1S1 as the gene responsible for the human EKV3 syndrome and demonstrate a critical role of AP1S1 in development of epithelial cells, pigmentation and spinal neurons in the zebrafish. |
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