ptk7 Mutant Zebrafish Models of Congenital and Idiopathic Scoliosis Implicate Dysregulated Wnt Signalling in Disease

Nat Commun. 2014 Sep 3;5:4777. doi: 10.1038/ncomms5777.

Abstract

Scoliosis is a complex genetic disorder of the musculoskeletal system, characterized by three-dimensional rotation of the spine. Curvatures caused by malformed vertebrae (congenital scoliosis (CS)) are apparent at birth. Spinal curvatures with no underlying vertebral abnormality (idiopathic scoliosis (IS)) most commonly manifest during adolescence. The genetic and biological mechanisms responsible for IS remain poorly understood due largely to limited experimental models. Here we describe zygotic ptk7 (Zptk7) mutant zebrafish, deficient in a critical regulator of Wnt signalling, as the first genetically defined developmental model of IS. We identify a novel sequence variant within a single IS patient that disrupts PTK7 function, consistent with a role for dysregulated Wnt activity in disease pathogenesis. Furthermore, we demonstrate that embryonic loss-of-gene function in maternal-zygotic ptk7 mutants (MZptk7) leads to vertebral anomalies associated with CS. Our data suggest novel molecular origins of, and genetic links between, congenital and idiopathic forms of disease.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Cell Adhesion Molecules / genetics*
  • Cell Adhesion Molecules / metabolism
  • Disease Models, Animal*
  • Embryo, Nonmammalian
  • Female
  • Gene Expression Regulation, Developmental
  • Humans
  • Inheritance Patterns
  • Male
  • Mutation
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Scoliosis / congenital
  • Scoliosis / genetics*
  • Scoliosis / metabolism
  • Scoliosis / pathology
  • Signal Transduction
  • Spine / growth & development
  • Spine / metabolism
  • Spine / pathology
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Zebrafish / genetics*
  • Zebrafish / growth & development
  • Zebrafish / metabolism
  • Zebrafish Proteins

Substances

  • Cell Adhesion Molecules
  • Wnt Proteins
  • Zebrafish Proteins
  • PTK7 protein, human
  • Receptor Protein-Tyrosine Kinases
  • ptk7b protein, zebrafish