In Shakespeare’s play, Julius Caesar, there is this line: “The fault, dear Brutus, is not in our stars, but in ourselves.” When it comes to inherited blindness, the prevailing school of thought is that genetic variants are at fault in cases of inherited blindness. Another school of thought is that modifier genes, in and of themselves, do not cause disease but can lessen or worsen it. Therefore, finding these modifier genes can help detect disease and develop treatments. Medical research challenges long-held ideas and seeks to learn what is happening at the genetic level in order to treat disease.
Not In and of Themselves
Scientists at Massachusetts General Brigham studied genes in public biobanks to see whether the genes that cause inherited retinal disease do so with almost 100 percent certainty. What they found is that these genes cause disease only 30 percent of the time.
For more than 100 years, the standard view in genetics has been that rare inherited diseases are caused by errors in individual genes. This has been supported by many years of studies involving patients and families affected by genetic diseases.
Scientists found that the number of people in the general population with genetic variants associated with inherited retinal diseases is higher than previously known. Yet, the number of those who actually have these diseases is lower than expected. The reason for this can be traced to bias, since most genetic studies take place in clinics and include people who have inherited disease or are affected by it. The development of volunteer biobanks allows for the study of genetic diseases across a larger and more diverse population, offers new resources for genetic studies, and reduces bias when studying rare genetic diseases.
Researchers used two biobanks, the National Institutes of Health’s All of Us Research Program (AoU) and the UK Biobank (UKB), to learn how often certain genetic variants lead to inherited retinal diseases. When they used a strict set of International Classification of Diseases (ICD) diagnostic codes from AoU health data, they found that only 9.4 percent of those in the AoU group had inherited retinal disease. When they used a broader set of ICD codes, only 28.1 percent of individuals had inherited retinal disease.
Scientists looked at the data from the UKB and found similar results. Among individuals who had inherited retinal disease variants, a range of 16.1 to 27.9 percent had inherited retinal disease. Participant demographics such as smoking, socioeconomic status, and even comorbidities did not predict the likelihood that inherited retinal disease would occur.
All of this indicates that more than just a particular gene is needed for the development of an inherited disease. Rather, additional genetic or environmental modifiers are part of the process. The information gathered from this study may influence how genetic tests are performed and can help in the development of treatments for genetic diseases. This approach is already being used successfully in diseases such as familial hypercholesterolemia.
Finding the Culprit
What do you do when it is known that a certain gene causes a disease, but you do not know what, if anything, the modifier genes do? The short answer is that you do research to learn more.
Scientists at the University of Alabama at Birmingham wanted to find the modifier genes for the hereditary eye disorder retinitis pigmentosa type 59 (RP59). This disease appears in a person’s late teens and slowly causes blindness by attacking the retina at the back of the eye. It is caused by a single nucleotide change that alters one amino acid in the gene that encodes dehydrodolichyl diphosphate synthase (DHDDS). DHDDS is part of a two-subunit enzyme that is needed for protein glycosylation, the covalent addition of carbohydrate to a protein.
The DHDDS mutation in RP59 leads to changes in synaptic transmission and retinal degeneration. Still, this disease does not cause problems elsewhere in the body. Protein N-glycosylation and other protein glycosylation pathways require more than 35 enzymes. These protein modifications are necessary for the function of all cells in the body.
Researchers studied 11 RP59 patients who had identical disease-causing point mutations in DHDDS. They examined five other genes involved in protein N-glycosylation to look for evidence of a phenotype (observable traits) modifier effect. Of the genes they studied, only one, ALG6, showed a change in its genetic sequence associated with an altered phenotype in RP59 patients. The ALG6 variant changes amino acid number 304 in this protein from phenylalanine to serine.
Five of the RP59 patients had only two different alleles. The remaining six patients did not have a DNA sequence variation in either allele of their ALG6 genes. There were three control subjects, people without RP59, to show that the ALG6 variant was not pathological by itself. One control subject lacked the ALG6 variant in both copies of the ALG6 gene. The other two were heterozygous and homozygous for the ALG6 variant.
The research showed that one factor analyzed, extra-macular rod sensitivity loss, delayed peripheral rod degeneration for more than 30 years in patients who were heterozygous for the ALG6 variant. In addition, a tendency was seen in three other parameters that indicated diminished macular cone photoreceptor health in individuals who had the heterozygous ALG6 variant.
What these results show is a potential deficit in macular cone function and the preservation of peripheral rod health in RP59 patients who co-express a heterozygous phenylalanine-304-to-serine mutation in ALG6. This research represents the beginning of precision medicine that connects big science and AI-driven genetic analysis.
These projects at Massachusetts General Brigham and the University of Alabama at Birmingham show that it takes more than one set of genes to cause disease. Yet, these projects are not the end of the story. The work done at Massachusetts General Brigham is now being used to treat other diseases. Research done at the University of Alabama at Birmingham is laying the groundwork for precision medicine. What was learned at both institutions will inform future research and lead to treatments that improve outcomes.