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Mutations in KIF7 implicated in idiopathic scoliosis in humans and axial curvatures in zebrafish
Author(s) -
Terhune Elizabeth A.,
Cuevas Melissa T.,
Monley Anna M.,
Wethey Cambria I.,
Chen Xiaomi,
Cattell Maria V.,
Bayrak Melisa N.,
Bland Morgan R.,
Sutphin Brittan,
Trahan George Devon,
Taylor Matthew R. G.,
Niswander Lee A.,
Jones Kenneth L.,
Baschal Erin E.,
Antunes Lilian,
Dobbs Matthew,
Gurnett Christina,
Appel Bruce,
Gray Ryan,
Hadley Miller Nancy
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24162
Subject(s) - ciliopathies , cilium , biology , zebrafish , genetics , exome sequencing , penetrance , exome , phenotype , bioinformatics , gene
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.