Genetic roots of adolescent scoliosis discovered
Scientists in Japan have identified a gene that is linked to susceptibility to adolescent idiopathic scoliosis, which affects tens of millions of children worldwide but has no known cause.
The research, published in the American Journal of Human Genetics, details how the susceptibility gene is associated with increased expression of the protein BNC2, which is in turn regulated by another protein called YY1. The work could help with the development of new targets for therapeutic intervention for the disease.
“AIS is a complex and mysterious disease with awkward spinal deformities that can be a nightmare for affected people,” explained team leader Shiro Ikegawa of the RIKEN Center for Integrative Medical Sciences. “We were excited to find a single nucleotide polymorphism located on human chromosome number nine that is significantly associated with the disease.”
The discovery began with a genome-wide association study using more than 10,000 volunteers with and without scoliosis. The researchers identified a single nucleotide polymorphism (SNPs) in two independent scoliosis populations – one in Japan and one in China – and determined its location near the part of the DNA that codes for the protein BNC2.
Using quantitative RT-PCR, they found that in humans BNC2 is most highly expressed in the uterus, spinal cord, bone, and cartilage. “This result told us that we were on the right track,” said Ikegawa, “and evidence that the SNP variation associated with the disease led to higher levels of BNC2 expression told us that this SNP has the potential to regulate expression of BNC2.”
The team tested this hypothesis and found that not only was BNC2 expression triggered by the protein YY1, which binds to the DNA around the SNP, but that for genes with the at-risk SNP variant, the amount of BNC2 produced when YY1 was present was much greater than for genes with the non-risk variant.
The BNC2 gene is highly conserved across diverse species, and plays roles in a variety of tissues. To test how over-expression of BNC2 affects development, the team expressed it in zebrafish embryos and found that it resulted in severe body curvature that was positively correlated to the amount of BNC2.
These results and the abundance of BNC2 in the human spine and bones make it likely that adolescents with the disease-associated SNP variant may begin to produce excess BNC2 at puberty if other genetic or environmental factors are also present.
The next step is to understand how BNC2 causes scoliosis and why it is so much more prevalent in women than in men.
“The expression of BNC2 in the uterus and changes that occur during puberty could help explain the large sex difference,” explained Ikegawa. “Additionally, knowing what genes are downstream of BNC2 will provide us with potential targets for therapeutic interventions.”
Ogura, Y., Kou, I., Miura, S., et al. (2015) A functional SNP in BNC2 is associated with adolescent idiopathic scoliosis. Am. J. Human Genet. doi: 10.1016/j.ajhg.2015.06.012.