Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency

Anderson, R.A., Schwalbach, K.T., Mui, S.R., LeClair, E.E., Topczewska, J.M., Topczewski, J.
Disease models & mechanisms   13(6): (Journal)
Registered Authors
Anderson, Rebecca, LeClair, Elizabeth E., Mui, Stephanie, Schwalbach, Kevin, Topczewska, Jolanta, Topczewski, Jacek
Cholesterol, Chondrodysplasia punctata, Lss, Msmo1, Skeletal dysplasia, Zebrafish
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Bone Diseases, Developmental/genetics
  • Bone Diseases, Developmental/metabolism*
  • Bone Diseases, Developmental/pathology
  • Bone and Bones/metabolism*
  • Bone and Bones/pathology
  • Cholesterol/biosynthesis*
  • Chondrocytes/metabolism*
  • Chondrocytes/pathology
  • Collagen Type X/genetics
  • Collagen Type X/metabolism
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Intramolecular Transferases/genetics
  • Intramolecular Transferases/metabolism
  • Liver/metabolism*
  • Mixed Function Oxygenases/genetics
  • Mixed Function Oxygenases/metabolism
  • Mutation
  • Phenotype
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
32430393 Full text @ Dis. Model. Mech.
Human disorders of the post-squalene cholesterol biosynthesis pathway frequently result in skeletal abnormalities, yet our understanding of the mechanisms involved is limited. In a forward genetic approach, we have found that a late-onset skeletal mutant, named kolibernu7 , is the result of a cis-acting regulatory mutation leading to loss of methylsterol monooxygenase 1 (msmo1) expression within prehypertrophic chondrocytes. Generated msmo1nu81 knockdown mutation resulted in lethality at larva stage. We demonstrated this is a result of both cholesterol deprivation and sterol intermediate accumulation by creating a mutation eliminating activity of Lanosterol synthase (Lss). Our results indicate that double lssnu60;msmo1nu81 and single lssnu60 mutants survive significantly longer than msmo1nu81 homozygotes. Liver-specific restoration of either Msmo1 or Lss in corresponding mutant backgrounds suppresses larval lethality. Rescued mutants develop dramatic skeletal abnormalities, with a loss of Msmo1 activity resulting in a more severe patterning defect of a near-complete loss of hypertrophic chondrocytes marked by col10a1 expression. Our analysis suggests that hypertrophic chondrocytes depend on endogenous cholesterol synthesis, and blocking C4 demethylation exacerbates the cholesterol deficiency phenotype. Our findings offer new insight into the genetic control of bone development and provide new zebrafish models for human disorders of the cholesterol biosynthesis pathway.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes