NEW YORK (GenomeWeb News) – Genes coding for the components of ion channels are just as likely to contain common, rare, and even potentially damaging changes in healthy individuals as they are in individuals with sporadic idiopathic epilepsy, according to a study appearing online today in Cell.
The findings hint at a complicated model for understanding diseases based on alterations to ion channel genes. And, researchers say, the pattern suggests that genetic testing for epilepsy likely can't rely on analyses of individual ion channel genes in isolation.
"Rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity," senior author Jeffrey Noebels, a neurology, neuroscience and molecular and human genetics researcher at Baylor College of Medicine, and co-authors wrote, "revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on other variants with which they are combined."
Ion channels, which contribute to signaling and excitability across the membranes of cells and their organelles, have been implicated in a range of rare Mendelian diseases, particularly those involving loss of membrane excitability.
Nevertheless, the study authors explained, many of the more than 400 or so voltage- or ligand-gated ion channel genes found in humans so far remain poorly understood or uncharacterized.
"Their central position in the biology and therapy of excitability disorders, combined with the imminent arrival of gene-directed medicine, provides compelling reasons to explore genomic variation in this exemplary gene set in order to correctly diagnose, predict, and treat a broad spectrum of common human disease," they wrote.
The researchers decided to look at genetic variation in ion channel coding regions in seemingly healthy individuals and in individuals with sporadic idiopathic epilepsy — forms of the seizure condition stemming from unknown genetic causes.
To do this, Noebels and his colleagues used the Sanger approach to sequence the exons of 237 genes coding for ion channel sub-units in 152 individuals with idiopathic epilepsy and 139 unaffected controls.
When they compared the coding sequences for these genes — which were selected for their previous ties to disease or phylogenetic ties to potentially pathogenic ion channel genes — the team found 11,102 SNPs, including nearly 3,100 that were subsequently validated.
Of these, 989 variants — 415 non-synonymous, nine nonsense, and 351 synonymous SNPs — had not been reported before. Many of the newly identified SNPs were rare, turning up in less than one percent of those tested, though all of the individuals tested had some ion channel gene SNPs.
Rather than finding an excess of rare variants or missense mutations in the epilepsy group, though, the team found comparable levels of these changes in both groups, suggesting that the consequences of potentially damaging mutations depend on the larger context in which they're found.
And when they looked specifically at 17 genes that have been linked to a familial form of epilepsy, the researchers found that nearly 67 percent of control individuals carried missense mutations in at least one of the genes. While that was lower than the level seen in the epilepsy group, where more than 96 percent of individuals had a mutation in one of the genes, it did support the notion that other genes modify the consequences of mutations to the disease-associated ion channel genes.
"We observed remarkable genetic complexity and overlapping patterns of both rare and common variants in known excitability disease genes across both populations, indicating that the potential for clinical expression of these common disorders is embedded in the fabric of all human genomes," the researchers explained.
Those involved in the study argue that the results so far suggest that predicting individual disease risk based on ion channel mutation and variation data will likely require a combination of both genomic and proteomic profiles, as well computer models that accurately depict the dynamic nature of the relevant genetic interactions.
"We conclude that epilepsy may arise from a complex mixture of altered channels, and may be prevented by other channels working in the background," Noebels said in a statement.
"We now know the profile of these channel variations is more important than the presence of any single ion channel defect," he added, "and that understanding the meaning of the profile and applying it to patients will require the skills not only of neurologists, but also bioinformatics specialists and experts in devising computational models of disease."