Mutations in KIF7 implicated in idiopathic scoliosis in humans and axial curvatures in zebrafish

Elizabeth A. Terhune, Melissa T. Cuevas, Anna M. Monley, Cambria I. Wethey, Xiaomi Chen, Maria V. Cattell, Melisa N. Bayrak, Morgan R. Bland, Brittan Sutphin, George Devon Trahan, Matthew R.G. Taylor, Lee A. Niswander, Kenneth L. Jones, Erin E. Baschal, Lilian Antunes, Matthew Dobbs, Christina Gurnett, Bruce Appel, Ryan Gray, Nancy Hadley Miller

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish
Pages (from-to)392-407
Number of pages16
JournalHuman mutation
Issue number4
StatePublished - Apr 2021


  • KIF7
  • exome sequencing
  • genetic variants
  • idiopathic scoliosis
  • zebrafish


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