@article{5832a6c03d1b43e79e842c3de74e1f14,
title = "Mutations in KIF7 implicated in idiopathic scoliosis in humans and axial curvatures in zebrafish",
abstract = "Idiopathic scoliosis (IS) is a spinal disorder affecting up to 3% of otherwise healthy children. IS has a strong familial genetic component and is believed to be genetically complex due to significant variability in phenotype and heritability. Previous studies identified putative loci and variants possibly contributing to IS susceptibility, including within extracellular matrix, cilia, and actin networks, but the genetic architecture and underlying mechanisms remain unresolved. Here, we used whole-exome sequencing from three affected individuals in a multigenerational family with IS and identified 19 uncommon variants (minor allele frequency < 0.05). Genotyping of additional family members identified a candidate heterozygous variant (H1115Q, G>C, rs142032413) within the ciliary gene KIF7, a regulator within the hedgehog (Hh) signaling pathway. Resequencing of the second cohort of unrelated IS individuals and controls identified several severe mutations in KIF7 in affected individuals only. Subsequently, we generated a mutant zebrafish model of kif7 using CRISPR-Cas9. kif7co63/co63 zebrafish displayed severe scoliosis, presenting in juveniles and progressing through adulthood. We observed no deformities in the brain, Reissner fiber, or central canal cilia in kif7co63/co63 embryos, although alterations were seen in Hh pathway gene expression. This study suggests defects in KIF7-dependent Hh signaling, which may drive pathogenesis in a subset of individuals with IS.",
keywords = "KIF7, exome sequencing, genetic variants, idiopathic scoliosis, zebrafish",
author = "Terhune, {Elizabeth A.} and Cuevas, {Melissa T.} and Monley, {Anna M.} and Wethey, {Cambria I.} and Xiaomi Chen and Cattell, {Maria V.} and Bayrak, {Melisa N.} and Bland, {Morgan R.} and Brittan Sutphin and Trahan, {George Devon} and Taylor, {Matthew R.G.} and Niswander, {Lee A.} and Jones, {Kenneth L.} and Baschal, {Erin E.} and Lilian Antunes and Matthew Dobbs and Christina Gurnett and Bruce Appel and Ryan Gray and {Hadley Miller}, Nancy",
note = "Funding Information: Exome sequencing was completed using funds donated by the LARRK Foundation. NHM's laboratory is supported by NIH/NIAMS R01AR068292. Additional support was provided by Rose Brown Endowment Funds and Children's Hospital of Colorado Research Institute. This study used the REDCap database and the Colorado Clinical and Translational Sciences Institute, which are supported by Colorado CTSA Grants UL1TR002535, KL2TR002534, and TL1TR002533. Exome sequencing was completed at the University of Colorado Denver Genomics and Microarray Core Facility with Bifeng Gao and Katrina Diener. Micro‐computed tomography scans of the zebrafish brain were obtained at the University of Texas High‐Resolution CT Facility by Jessica Maisano. Sequencing of these samples was supported by NIH NIAMS 1R01AR067715‐01 (Matthew Dobbs and Christina Gurnett). The authors would like to thank Christina Kearns, Curtis Boswell, and Christine Archer for their helpful advice regarding zebrafish husbandry. The data used for the analyses described in this paper were obtained from the database of Genotypes and Phenotypes, at http://www.ncbi.nlm.nih.gov/gap . Genotype and phenotype data for the Adolescent Idiopathic Scoliosis 1000 Exomes Study were provided by Dr. Matthew Dobbs of Washington University School of Medicine. Patient samples for this study were provided by investigators at Washington University (Matthew Dobbs), Shriners Hospital for Children (Matthew Dobbs), University of Colorado (Nancy Hadley Miller), University of Iowa (Jose Morcuende), University of Wisconsin (Philip Giampietro), Hospital for Special Surgery (Cathleen Raggio), and Texas Scottish Rite Hospital (Carol Wise). Funding Information: Exome sequencing was completed using funds donated by the LARRK Foundation. NHM's laboratory is supported by NIH/NIAMS R01AR068292. Additional support was provided by Rose Brown Endowment Funds and Children's Hospital of Colorado Research Institute. This study used the REDCap database and the Colorado Clinical and Translational Sciences Institute, which are supported by Colorado CTSA Grants UL1TR002535, KL2TR002534, and TL1TR002533. Exome sequencing was completed at the University of Colorado Denver Genomics and Microarray Core Facility with Bifeng Gao and Katrina Diener. Micro-computed tomography scans of the zebrafish brain were obtained at the University of Texas High-Resolution CT Facility by Jessica Maisano. Sequencing of these samples was supported by NIH NIAMS 1R01AR067715-01 (Matthew Dobbs and Christina Gurnett). The authors would like to?thank Christina Kearns, Curtis Boswell, and Christine Archer for their helpful advice regarding zebrafish husbandry. The data used for the analyses described in this paper were obtained from the database of Genotypes and Phenotypes, at http://www.ncbi.nlm.nih.gov/gap. Genotype and phenotype data for the Adolescent?Idiopathic Scoliosis 1000 Exomes Study were provided by Dr. Matthew Dobbs of Washington University School of Medicine. Patient samples for this study were provided by investigators at Washington University?(Matthew Dobbs), Shriners Hospital for Children?(Matthew Dobbs), University of Colorado (Nancy Hadley Miller), University of Iowa (Jose Morcuende), University of Wisconsin (Philip Giampietro), Hospital for Special Surgery (Cathleen Raggio), and Texas Scottish Rite Hospital (Carol Wise). Publisher Copyright: {\textcopyright} 2020 Wiley Periodicals LLC",
year = "2021",
month = apr,
doi = "10.1002/humu.24162",
language = "English",
volume = "42",
pages = "392--407",
journal = "Human Mutation",
issn = "1059-7794",
number = "4",
}