PUBLICATION

Zebrafish Fukutin family proteins link the unfolded protein response with dystroglycanopathies

Authors
Lin, Y.Y., White, R.J., Torelli, S., Cirak, S., Muntoni, F., and Stemple, D.L.
ID
ZDB-PUB-110221-8
Date
2011
Source
Human molecular genetics   20(9): 1763-75 (Journal)
Registered Authors
Lin, Yung-Yao, Stemple, Derek L.
Keywords
none
MeSH Terms
  • Animals
  • Disease Models, Animal*
  • Female
  • Gene Knockdown Techniques
  • Glycosylation
  • Glycosyltransferases/genetics
  • Glycosyltransferases/metabolism*
  • Humans
  • Male
  • Muscular Dystrophies/embryology
  • Muscular Dystrophies/genetics
  • Muscular Dystrophies/metabolism*
  • Protein Transport
  • Unfolded Protein Response*
  • Zebrafish*/genetics
  • Zebrafish*/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
21317159 Full text @ Hum. Mol. Genet.
Abstract
Allelic mutations in putative glycosyltransferase genes, fukutin and fukutin-related protein (fkrp), lead to a wide range of muscular dystrophies associated with hypoglycosylation of α-Dystroglycan, commonly referred to as dystroglycanopathies. Defective glycosylation affecting Dystroglycan-ligand interactions is considered to underlie the disease pathogenesis. We have modelled dystroglycanopathies in zebrafish using a novel loss-of-function dystroglycan allele and by inhibition of Fukutin family protein activities. We show that muscle pathology in embryos lacking Fukutin or FKRP is different from loss of Dystroglycan. In addition to hypoglycosylated α-Dystroglycan, knockdown of Fukutin or FKRP leads to a notochord defect and a perturbation of laminin expression before muscle degeneration. These are a consequence of ER stress and activation of the unfolded protein response (UPR), preceding loss of Dystroglycan-ligand interactions. Together, our results suggest that Fukutin family proteins may play important roles in protein secretion and that the UPR may contribute to the phenotypic spectrum of some dystroglycanopathies in humans.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes