ALG6 acts as a modifier gene in the inherited genetic eye disease retinitis pigmentosa 59

Using a panel of 11 RP59 patients who all have an identical, disease-causing point mutation in DHDDS, researchers from the University of Alabama, Birmingham, examined five other genes involved in protein N-glycosylation for evidence of a phenotype-modifier effect. A modifier gene is one that has genetic variants such as single nucleotide changes that differ from the most common sequence in the population. These variants do not cause disease by themselves but can lessen or exacerbate a different genetic disease phenotype by unknown mechanisms.

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.