What if it’s a modifier gene that causes problems with vision? What’s so troublesome about a modifier gene? It has a variant, such as a single nucleotide change, that differs from the common sequence. The variant doesn’t cause disease by itself, but it can influence the observable characteristics of a genetic disease through mechanisms that aren’t fully understood.
Modifier Genes Affecting Retinitis Pigmentosa
Research at the lab of Steven Pittler, PhD, at the University of Alabama at Birmingham focused on identifying modifier genes for retinitis pigmentosa type 59. This type of retinitis pigmentosa starts in a person’s late teens and causes blindness over time by damaging the retina.
Retinitis pigmentosa type 59 is caused by a single nucleotide change that alters one amino acid in the gene that encodes the enzyme dehydrodolichyl diphosphate synthase. This enzyme is a two-subunit enzyme that is required for adding carbohydrates to proteins. The mutation in retinitis pigmentosa type 59 alters synaptic transmission and leads to retinal degeneration. Yet, this disease does not cause problems elsewhere in the body.
Researchers studied the genes from 11 retinitis pigmentosa type 59 patients who had the disease-causing mutation in the enzyme dehydrodolichyl diphosphate synthase. They also looked at five other genes involved in protein modifications for signs of a phenotype-modifier effect, which is a genetic, biochemical, or functional interaction with one or more target genes or gene product. Of the five genes only one—known as ALG6—showed a variation in its genetic sequence that correlated with the altered phenotypes among the retinitis pigmentosa type 59 patients. The ALG6 variant changes amino acid number 304 in the ALG6 protein from phenylalanine to serine.
Five out of the 11 patients had two different forms of ALG6 modifier variant. The remaining six had no DNA sequence variation in either form of their ALG6 genes. Scientists also studied data collected for over 50 years for six clinical parameters of retinal function and structure in the 11 retinitis pigmentosa type 59 patients. One parameter, the extra-macular rod sensitivity loss, delayed peripheral rod degeneration for over 30 years in patients with two different alleles of the ALG6 variant. This was observed in three other parameters that indicated reduced macular cone photoreceptor health in individuals with the variant.
This research demonstrates that different forms of the modifier gene may lead to the variation seen in genetic diseases like retinitis pigmentosa type 59. More work will be done to learn more about how the variations affect different regions in the retina. The work of Pittler’s lab marks an early effort in integrating big data science with artificial intelligence-driven analysis of genetic groups.
The research projects mentioned in Parts One and Two highlight the complexity of the role genetics play in vision diseases. They also show the potential of the use of genes and gene modifiers as treatment targets. While research is ongoing, the information gathered can lead to a greater understanding of how vision diseases develop and, ultimately, to therapies that improve outcomes.