Will you pass scoliosis onto your children?
Genetic Breakthrough for Idiopathic Scoliosis– What Impact (if any) Will it Have?
An international France-Canada research team announced their discovery of the first gene causing scoliosis occurring in families.
“To date, many genes have been suspected of causing scoliosis amongst different populations, but the gene that causes the familial form of the disease remained unknown. Our discovery of this first causative gene is due to the support of the Fondation Yves Cotrel and our international teamwork, in particular with leading co-author Dr. Patrick Edery of CHU de Lyon hospital and Dr. Pierre Drapeau of the CRCHUM.”
– Dr Florina Moldovan of the University of Montreal and the CHU Sainte Justine research hospital (leading co-author)
Through DNA exome sequencing (see video below), their team was able to identify a variation in the POC5 gene in samples collected from a large French family with several members affected by idiopathic scoliosis. Variations of the POC5 gene were also found in scoliotic families and even in individuals who were the first in their family to have scoliosis.
“The POC5 gene encodes for a centrosomal protein involved in microtubule-organising centres and cellular polarity. The pathogenicity of POC5 variants was documented by using the zebrafish, a well-established genetic animal model that has a spine.”
– Dr. Shunmoogum (Kessen) Patten, CHU Sainte-Justine and CHUM research centres
This demonstrated that over-expression of mutated human POC5 gene led to the rotational deformation of the anterior-posterior axis (front to back) of the spine in 50% of the zebrafish embryos. Deformations that are similar to those observed in scoliosis patients. This suggests that the mutations are dominant, confirming the results found in humans.
The centrosomal protein, that POC5 encodes for, is strongly expressed within very precise structures in the midbrain (associated with motor control). This leads the research team to believe that there is an association between the brain and idiopathic scoliosis–a idea that is not novel (the neuromuscular reeducation aspect of our own scoliosis treatment program operates under this assumption).
“This is a very heterogenous disease and probably more than one gene is required for disease expression. This discovery has enabled the identification of the first causative gene and represents an important step towards decoding its genetic causes.”
– Dr. Moldovan
“This crucial first step will open the door to future studies that will identify the complementary genes and pathways that play a role in scoliosis in other populations.In particular, a full portrait of genetic events would enable the perfecting of effective preventative methods and strategies for understanding scoliosis.”
– Dr. Drapeau
Sources [1, 2] “Functional variants of POC5 identified in patients with idiopathic scoliosis” in The Journal of Clinical Investigation on February 2, 2015.
A 2013 study from the above authors focused more upon the expression and interaction of genes, leaning toward the epigenetic nature of scoliosis. Epigenetics studies cellular and physiological trait variations that are not caused by changes in the DNA sequence. It is alterations in the transcriptional potential of a cell that may or may not be heritable. Unlike genetics based on changes to DNA sequence (the genotype), the changes in gene expression or cellular phenotype of epigenetics have other causes. Epi comes from the Greek meaning “over, outside of, or around”. As an organism grows and develops, chemical reactions activate and deactivate parts of the genome at specific times and in specific locations. Epigenetics is the study of these chemical reactions and the factors that influence them. It is universally accepted that scoliosis is not a Mendelian disorder (any genetic disease which follows simple mendelian patterns of inheritance), and does not occur because of a defect in a single gene.
Studies like these are vital in scoliosis research. Genetic research was behind the ScoliScore AIS Prognostic Test. In 2003 researchers took DNA samples from over 9,000 patients from 85 clinics worldwide and identified 53 genetic markers (or mistakes in the DNA) that are linked to AIS– 28 signs in DNA that an AIS curve will progress (progressive genes), and 25 signs in DNA that an AIS curve will not progress (protective genes). Lab workers read each of those 53 genetic markers for a patient and assign them a “ScoliScore”—a numerical value that falls into one of three categories, mild risk, intermediate risk, or severe risk of curve progression.
ScoliScore AIS Prognostic Test was made available in 2009 as a genetic test. It was used analyze the DNA of male and female patients diagnosed with Mild (10–25° Cobb angle) Adolescent Idiopathic Scoliosis (AIS) who are between 9 to 13 years of age and who are self-reported as Caucasian (including patients of North American, South American, European, Eastern European, Middle Eastern, or South West Asian descent). As of 2016, the test is no longer available. Read More....
Conversely, research like this can take years to have any influence–if at all. In 2007 researchers at the Texas Scottish Rite Hospital for Children identified the first gene even associated with idiopathic scoliosis, CHD7. It was the result of a 10-year study. In addition their team identified two additional genes in 2011 , CHL1 and DSCAM, that play a role in the neurological and spinal systems. Eight years later, their findings have had little-to-no impact on how scoliosis is diagnosed or managed.
The Canadian study is interesting and possibly revolutionary, but will it have an impact? The researchers have begun further studies into whether this “risk-modifying allele” (the variant form of the gene) could also cosegregate in the french test families. Cosegregation refers to the transmission of two or more linked genes on a chromosome to the same daughter cell, leading to the inheritance of the two genes at the same time.
“Such a modifier allele may be located on 3q12.3 in family F2, where the same chromosome 3q12.3 haplotype segregates in all 11 affected patients, but not in the unaffected carrier.”
However, because the risk-modifying allele is not located on the same chromosome in another test family, they suggest that the modifier allele may be different from family to family.
“If we assume that at least 2 genes are required for disease expression, the combination of 2 rare variants with low marginal penetrance could confer high disease penetrance in carriers. This type of model could explain both the phenotypic and genetic observations in families F2 and F19 and why large multiplex IS families are so rare, as the disease recurrence risk in the sibship of a patient would be less than or equal to one-fourth.”
They suggest that additional studies with larger populations of different ethnicities are needed to determine the contribution of POC5 variants to idiopathic scoliosis and the pervasiveness in the general population. An unfortunate aspect of research is that the results only pertain to the very specific test population and not the entire population, otherwise there would be too many additional factors that could influence results. For examples, the ScoliScore ScoliScore AIS Prognostic Test is only used for Adolescent Idiopathic Scoliosis patients ages 9-13 years, who self-reported Caucasian, who have mild curves (10° – 25° Cobb angle) and are from North American, South American, European, Eastern European, or the Middle Eastern, because that was the test pool population. That is why it is so important for research like this and for the research that builds on preliminary studies like this. Only time will tell what becomes of it..