University of Alabama at Birmingham scientists discovered how modifier genes affect progression of the inherited retinal disease RP59, a form of retinitis pigmentosa. Mutations in modifier genes do not cause disease by themselves but can lessen or exacerbate a different genetic disease phenotype.

Using a panel of 11 patients who all have an identical mutations in the gene that causes RP59, the researchers examined five other genes for evidence of a phenotype-modifier effect.

Of the five genes, only one, ALG6, showed a variation in its genetic sequence that correlated with altered phenotypes among the RP59 patients. The ALG6 variant changes amino acid number 304 in the ALG6 protein from phenylalanine to serine.

The researchers examined data collected over five decades for six clinical parameters of retinal function and structure in the 11 RP59 patients. The report published in the International Journal of Molecular Sciences shows that one parameter analyzed — extra-macular rod sensitivity loss — significantly delayed peripheral rod degeneration over 30 years in patients who were heterozygous for the ALG6 variant. Furthermore, a trend was observed in three other parameters that collectively suggested a diminished macular cone photoreceptor health in individuals heterozygous for the ALG6 variant.

“In this case, the consequences of the polymorphisms are counterintuitively complex in terms of rod and cone populations affected in different regions of the retina,” said Steven Pittler, Ph.D., at the University of Alabama at Birmingham, senior author of the study.