Researchers Identify Gene That Kickstarts Scoliosis

An overactive gene, called ladybird homeobox 1, was found to be the start of a genetic chain reaction that causes the spine to grow abnormally.

AsianScientist (Apr. 19, 2016) – People with scoliosis—a twisting of the spine that can occur as a birth defect or more commonly starts during the teen years—are now closer to a genetic explanation for their condition. An overactive gene, called ladybird homeobox 1 (LBX1), is the start of a genetic chain reaction that causes the spine to grow abnormally. These findings were published in PLOS Genetics.

“A genetic test called the ScoliScore AIS Prognostic Test already exists for adolescents recently diagnosed with scoliosis to predict if the curve of the spine will get worse, which can guide treatment decisions,” explained corresponding author, Professor Chisa Shukunami from the Department of Molecular Biology and Biochemistry at Hiroshima University.

“Studies like ours that identify genes important in causing scoliosis can help further develop this current prognostic test into a clinically predictive genetic test to identify scoliosis before symptoms occur.”

Scoliosis is a polygenetic disease—mutations in multiple genes are responsible, and environmental factors may also be relevant. The scientific community already knows that one set of molecules, called the Wnt/PCP signaling pathway, is partially responsible for twisting the spine in scoliosis. These research results reveal how the Wnt/PCP pathway becomes problematic and provide insights for restoring normalcy.

Too little activity of the LBX1 gene has no effect on development; on the flipside, the research team suspected that too much LBX1 activity might be problematic.

The scientists performed genetic experiments using zebrafish, a small freshwater fish common in research labs, to model scoliosis. Researchers genetically manipulated zebrafish so they had too much LBX1 and then observed how their spines grew. The timing of when too much LBX1 started was important for how the fish’s bodies developed.

What the researchers observed was that during embryonic development, groups of cells form a pattern of mirror images on either side of the body and eventually become many different parts of the spine.

In embryos injected with extra LBX1, the cells responsible for becoming the backbone and back muscles were wider than in healthy fish. Fish that survived long enough developed misshapen bones in their backs, which caused their scoliosis. Researchers believe this model represents the birth defect version of scoliosis in humans, because the bones are obviously misshapen.

Another group of zebrafish were genetically modified to express extra LBX1 throughout their entire lives, but only in some cells, making them what researchers call genetic mosaics. Some of these fish developed bones with the correct shape, but their spines still grew curved as they entered adulthood. This model is typical of the majority of human scoliosis cases, where there are no signs of problems until growth spurts just before or during adolescence. Adolescent idiopathic scoliosis affects 2-4 percent of all children aged 10 to 16.

Adolescent-onset scoliosis in humans is more common in girls, and interestingly, researchers noticed more of their female fish developed scoliosis than their male fish. The reasons for why females are more susceptible remains a mystery, but it does further support the strength of using this zebrafish model to study the genetic causes of scoliosis.

“Greater understanding of the genetic mechanisms that lead to adolescent-onset scoliosis is necessary before any genetic interventions for clinical treatments can be designed,” said Shukunami.

The article can be found at: Guo et al. (2016) 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.


Source: Hiroshima University; Photo: Shutterstock.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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