title: ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease.
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.
authors.affiliation: 1] Program in Developmental &Stem Cell Biology, The Hospital for Sick Children, 686 Bay Street, PGCRL 15-9712, Toronto, Ontario, Canada M5G 0A4 [2] Department of Molecular Genetics, The University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Madeline
authors.initials: M
authors.lastname: Hayes
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 2222 Welborn Street, Dallas, Texas 75219, USA.
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Gao
authors.affiliation: Mouse Imaging Centre (MICe), The Hospital for Sick Children, 25 Orde Street, Toronto, Ontario, Canada M5T 3H7.
authors.forename: Lisa X
authors.initials: LX
authors.lastname: Yu
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 2222 Welborn Street, Dallas, Texas 75219, USA.
authors.forename: Nandina
authors.initials: N
authors.lastname: Paria
authors.affiliation: 1] Mouse Imaging Centre (MICe), The Hospital for Sick Children, 25 Orde Street, Toronto, Ontario, Canada M5T 3H7 [2] Department of Medical Biophysics, The University of Toronto, Toronto, Ontario, Canada M5G 2M9.
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.affiliation: 1] Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 2222 Welborn Street, Dallas, Texas 75219, USA [2] Departments of Orthopedics, Pediatrics, McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75253, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
authors.affiliation: 1] Program in Developmental &Stem Cell Biology, The Hospital for Sick Children, 686 Bay Street, PGCRL 15-9712, Toronto, Ontario, Canada M5G 0A4 [2] Department of Molecular Genetics, The University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Brian
authors.initials: B
authors.lastname: Ciruna
mesh_terms: D000293:Adolescent; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D009154:Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012600:Scoliosis / Q000151:congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013131:Spine / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029961:Zebrafish Proteins
chemical_list: D015815:Cell Adhesion Molecules; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C096905:PTK7 protein, human; D020794:Receptor Protein-Tyrosine Kinases; C581480:ptk7b protein, zebrafish