Adolescent idiopathic scoliosis affects about two percent of the population. It’s the most common pediatric skeletal condition, but its cause remains unknown. A new study from Japan’s RIKEN Center for Integrative Medical Sciences and Keio University uncovers a link between scoliosis susceptibility and the gene that codes for the BNC2 protein, which appears in reproductive system tissues. This genetic discovery could represent a first step toward explaining why the condition is more prevalent in girls than boys.

Scoliosis is characterized by an abnormal, sideways curvature of the spine. Viewed from the back, a typical spine is straight, but when scoliosis develops, the spine will curve to the right or left, and in some cases, the spine may curve twice, resulting in a shape like the letter S. The term “idiopathic” simply means a particular condition has no known cause. Adolescent idiopathic scoliosis, then, refers to the development of scoliosis during the growth spurt typically experienced by boys and girls somewhere between ages 10 and their early teens. While boys and girls develop mild scoliosis at the same rate, as the National Institutes of Health website explains, girls are at higher risk of developing a more severe condition, in which the curve worsens and requires treatment.

Naturally, many researchers have wondered if some particular genetic variation, more common in girls, might influence the development of scoliosis.

Follow the SNPs

To begin the current study, Dr. Shiro Ikegawa, Laboratory for Bone and Joint Diseases at RIKEN, and his colleagues enlisted the help of more than 10,000 volunteers, some with and others without scoliosis. The researchers conducted a search of participants’ single nucleotide polymorphisms (SNPs, pronounced ‘snips’), which are the most commonly occurring genetic variations. A SNP may replace, for example, cytosine (C) with thymine (T) in a stretch of DNA. Because SNPs commonly are located in the DNA between genes, they often act as markers helping scientists locate genes associated with a particular disease.

After searching and discovering a SNP linked to scoliosis, then, the researchers investigated further and discovered this SNP was located near the DNA that codes for the protein BNC2. Using a special laboratory technique, the science team found BNC2 is most highly expressed in the uterus, spinal cord, bone, and cartilage.

“This result told us that we were on the right track,” Ikegawa stated in a press release.

Because the SNP variation led to higher levels of BNC2 expression, this suggested it might regulate expression of the protein. Testing this hypothesis, the science team saw the presence of one protein, YY1, triggered BNC2 expression. When present, YY1 caused more BNC2 to be produced in genes with the at-risk SNP variant than in genes with the non-risk SNP variant.

To test how over-expression of BNC2 affects development, Ikegawa and his colleagues expressed it in zebrafish embryos. This resulted in severe body curvature that was positively correlated to the amount of BNC2. This result 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 explain why scoliosis is more prevalent in women than in men. For now, Ikegawa and his colleagues theorize expression of BNC2 in the uterus combined with pubertal changes might explain the large sex difference. Ultimately, he and his colleagues plan to search for an appropriate treatment target to prevent the condition.

Source: Ogura E, Ikegawa S, et al. A functional SNP in BNC2 is associated with adolescent idiopathic scoliosis. American Journal of Human Genetics. 2015.