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

Autor: Terhune EA; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Cuevas MT; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Monley AM; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.; Musculoskeletal Research Center, Children's Hospital Colorado, Aurora, Colorado, USA., Wethey CI; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Chen X; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Cattell MV; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Bayrak MN; Department of Nutritional Sciences, Dell Pediatrics Research Institute, The University of Texas at Austin, Austin, Texas, USA., Bland MR; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Sutphin B; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Trahan GD; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Taylor MRG; Department of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Niswander LA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.; Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA., Jones KL; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Baschal EE; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Antunes L; Department of Orthopedics, Washington University School of Medicine, St. Louis, Missouri, USA., Dobbs M; Department of Orthopedics, Washington University School of Medicine, St. Louis, Missouri, USA., Gurnett C; Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA., Appel B; Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA., Gray R; Department of Nutritional Sciences, Dell Pediatrics Research Institute, The University of Texas at Austin, Austin, Texas, USA., Hadley Miller N; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.; Musculoskeletal Research Center, Children's Hospital Colorado, Aurora, Colorado, USA.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2021 Apr; Vol. 42 (4), pp. 392-407. Date of Electronic Publication: 2021 Feb 07.
DOI: 10.1002/humu.24162
Abstrakt: 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. kif7 co63/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 kif7 co63/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.
(© 2020 Wiley Periodicals LLC.)
Databáze: MEDLINE
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