PCR helps find the genetic roots of adolescent scoliosis

A team of Japanese researchers have used PCR to help to uncover genetic clues to the cause of adolescent idiopathic scoliosis, a disease that causes curvature of the spine. The results are published in the American Journal of Human Genetics.

Chromosome 9

Adolescent idiopathic scoliosis is the most common spinal deformity, and has no known cause. It affects tens of millions of children worldwide. This is a complex disease that causes awkward spinal deformities, and these can be a nightmare for affected people, according to Shiro Ikegawa.

The researchers, from the RIKEN Center for Integrative Medical Sciences, in collaboration with Keio University in Japan, had previously carried out a genome-wide association study (GWAS) in over 10,000 volunteers with and without scoliosis. They found two genetic loci that were associated with adolescent idiopathic scoliosis in this initial study. They then extended the GWAS with volunteers from China and Japan, increasing the number of people studied to 2,109 affected subjects and 11,140 control subjects. This confirmed the a connection with a locus on chromosome 9, including a single nucleotide polymorphism (SNP) in the gene that codes for the protein basonuclin-2 (BNC2), a zinc finger transcription factor.

“We were excited to find a single nucleotide polymorphism located on human chromosome number nine that is significantly associated with the disease,” says Ikegawa.

Using qPCR, the team found that the highest levels of expression of BNC2 in humans were in the uterus, spinal cord, bone, and cartilage.

“This result told us that we were on the right track,” says 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.”

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, affecting the spine curvature, 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,” explains Ikegawa. “Additionally, knowing what genes are downstream of BNC2 will provide us with potential targets for therapeutic interventions.”

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