PUBLICATION
Mutations in KIF7 Implicated in Idiopathic Scoliosis in Humans and Axial Curvatures in Zebrafish
- Authors
- Terhune, E.A., Cuevas, M.T., Monley, A.M., Wethey, C.I., Chen, X., Cattel, M.V., Bayrak, M.N., Bland, M.R., Sutphin, B., Devon Trahan, G., Taylor, M.R.G., Niswander, L.A., Jones, K.L., Baschal, E.E., Antunes, L., Dobbs, M., Gurnett, C., Appel, B., Gray, R., Miller, N.H.
- ID
- ZDB-PUB-210101-23
- Date
- 2020
- Source
- Human Mutation 42(4): 392-407 (Journal)
- Registered Authors
- Antunes, Lilian, Appel, Bruce, Gray, Ryan, Gurnett, Christina
- Keywords
- KIF7, Idiopathic scoliosis, exome sequencing, genetic variants, zebrafish
- MeSH Terms
-
- Animals
- Cilia/metabolism
- Humans
- Kinesins*/genetics
- Mutation
- Scoliosis*/genetics
- Zebrafish*/genetics
- Zebrafish Proteins
- PubMed
- 33382518 Full text @ Hum. Mutat.
Citation
Terhune, E.A., Cuevas, M.T., Monley, A.M., Wethey, C.I., Chen, X., Cattel, M.V., Bayrak, M.N., Bland, M.R., Sutphin, B., Devon Trahan, G., Taylor, M.R.G., Niswander, L.A., Jones, K.L., Baschal, E.E., Antunes, L., Dobbs, M., Gurnett, C., Appel, B., Gray, R., Miller, N.H. (2020) Mutations in KIF7 Implicated in Idiopathic Scoliosis in Humans and Axial Curvatures in Zebrafish. Human Mutation. 42(4):392-407.
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 ECM, cilia and actin networks, but the genetic architecture and underlying mechanisms remains unresolved. Here, we used whole exome sequencing from three affected individuals in a multigenerational family with IS and identified 19 uncommon variants (MAF <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 a 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 research suggests defects in KIF7-dependent Hh signaling may drive pathogenesis in a subset of individuals with IS. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping