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Previously, we identified an adolescent idiopathic scoliosis susceptibility locus near human  ladybird homeobox 1  ( LBX1 ) and  FLJ41350  by a genome-wide association study. Here, we characterized the associated non-coding variant and investigated the function of these genes. A chromosome conformation capture assay revealed that the genome region with the most significantly associated single nucleotide polymorphism (rs11190870) physically interacted with the promoter region of  LBX1-FLJ41350 . The promoter in the direction of  LBX1 , combined with a 590-bp region including rs11190870, had higher transcriptional activity with the risk allele than that with the non-risk allele in HEK 293T cells. The ubiquitous overexpression of human  LBX1  or either of the zebrafish  lbx  genes ( lbx1a ,  lbx1b , and  lbx2 ), but not  FLJ41350 , in zebrafish embryos caused body curvature followed by death prior to vertebral column formation. Such body axis deformation was not observed in transcription activator-like effector nucleases mediated knockout zebrafish of  lbx1b  or  lbx2 . Mosaic expression of  lbx1b  driven by the  GATA2  minimal promoter and the  lbx1b  enhancer in zebrafish significantly alleviated the embryonic lethal phenotype to allow observation of the later onset of the spinal curvature with or without vertebral malformation. Deformation of the embryonic body axis by  lbx1b  overexpression was associated with defects in convergent extension, which is a component of the main axis-elongation machinery in gastrulating embryos. In embryos overexpressing  lbx1b ,  wnt5b ,  a  ligand of the non-canonical Wnt/planar cell polarity (PCP) pathway, was significantly downregulated. Injection of mRNA for  wnt5b  or  RhoA , a key downstream effector of Wnt/PCP signaling, rescued the defective convergent extension phenotype and attenuated the  lbx1b -induced curvature of the body axis. Thus, our study presents a novel pathological feature of  LBX1  and its zebrafish homologs in body axis deformation at various stages of embryonic and subsequent growth in zebrafish.

plos genetics

Functional Investigation of a Non-coding Variant Associated with Adolescent Idiopathic Scoliosis in Zebrafish: Elevated Expression of the Ladybird Homeobox Gene Causes Body Axis Deformation