Evaluation of IRX Genes and Conserved Non-coding Elements in a Region on 5p13.3 Linked to Families with Familial Idiopathic Scoliosis and Kyphosis

Justice, C.M., Bishop, K., Carrington, B., Mullikin, J.C., Swindle, K., Marosy, B., Sood, R., Miller, N.H., Wilson, A.F.
G3 (Bethesda)   6(6): 1707-12 (Journal)
Registered Authors
Sood, Raman
IRX genes, conserved noncoding regions, idiopathic scoliosis, kyphoscoliosis, zebrafish transgenesis
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Chromosomes, Human, Pair 5*
  • Conserved Sequence*
  • Exons
  • Gene Expression
  • Genes, Reporter
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genotype
  • Homeodomain Proteins/chemistry
  • Homeodomain Proteins/genetics*
  • Humans
  • Kyphosis/genetics*
  • Polymorphism, Single Nucleotide
  • Scoliosis/genetics*
  • Zebrafish
27172222 Full text @ G3 (Bethesda)
Because of genetic heterogeneity present in idiopathic scoliosis, we previously defined clinical subsets (a priori) from a sample of families with idiopathic scoliosis to find genes involved with spinal curvature. Previous genome-wide linkage analysis of seven families with at least two individuals with kyphoscoliosis found linkage (p-value < 0.002) with a 3.5 mega base region on 5p13.3 containing only three known genes, IRX1, IRX2, and IRX4 In this study, the exons of IRX1, IRX2 and IRX4, the conserved non-coding elements in the region, and the exons of a non-protein coding RNA, LOC285577, were sequenced. No functional sequence variants were identified. An intra-familial test of association found several associated non-coding single nucleotide variants. The strongest association was with rs12517904 (p = 0.00004), located 6.5 kilo bases downstream from IRX1 In one family, the genotypes of nine variants differed from the reference allele in all individuals with kyphoscoliosis, and two of three individuals with scoliosis, but did not differ from the reference allele in all other genotyped individuals. One of these variants, rs117273909, was located in a conserved non-coding region that functions as an enhancer in mice. To test whether the variant allele at rs117273909 had an effect on enhancer activity, zebrafish transgenesis was performed with overlapping fragments of 198 and 687 base pairs containing either the wild type or the variant allele. Our data suggests that this region acts as a regulatory element; however, its size and target gene(s) need to be identified to determine its role in idiopathic scoliosis.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes