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Unraveling the role of modifier genes in retinitis pigmentosa Type 59: A study on ALG6 variant effects


In a recent study led by Steven Pittler, PhD, and his team at the University of Alabama Birmingham (UAB), the role of modifier genes in retinitis pigmentosa type 59 (RP59) was meticulously examined.

(Image Credit: AdobeStock/AlexCaelus)

(Image Credit: AdobeStock/AlexCaelus)

Modifier genes have genetic variants such as single nucleotide changes that differ from the most common sequence in the population, and these variants do not cause disease by themselves but can lessen or exacerbate a different genetic disease phenotype by unknown mechanisms.

Steven Pittler, PhD, a researcher at the University of Alabama Birmingham, has sought to find modifier genes for the hereditary eye disorder retinitis pigmentosa type 59 (RP59).

Starting in an individual's late teens, RP59 slowly causes blindness over years or decades by attacking the retina. RP59 is caused by a single nucleotide change that alters one amino acid in the gene that encodes dehydrodolichyl diphosphate synthase, or DHDDS. DHDDS is part of a two-subunit enzyme required for protein glycosylation, a covalent addition of carbohydrates to the protein.

According to a UAB news release, the DHDDS mutation in RP59 leads to alteration of synaptic transmission and retinal degeneration. However, the disease does not appear to cause problems anywhere else in the body.1

The researchers have found that protein N-glycosylation and other protein glycosylation pathways require more than 35 enzymes. These protein modifications are crucial for function in all cells of the body, including cell–cell recognition, immune response, extracellular matrix formation, ion and solute transport, and signal transduction.2

Using a panel of 11 RP59 patients with an identical, disease-causing point mutation in DHDDS, Pittler and the research team examined 5 other genes involved in protein N-glycosylation for evidence of a phenotype-modifier effect. Of the 5 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.

As part of the study, 5 RP59 patients were heterozygous for the ALG6 modifier variant, meaning they had two different alleles. The remaining 6 patients showed the most common allele sequence, meaning no DNA sequence variation in either allele of their ALG6 genes. To show that the ALG6 variant was non-pathogenic by itself, the researchers also included 3 control subjects — people without RP59 (no change from the most common sequence of DHDDS). One control lacked the ALG6 variant in both copies of the ALG6 gene, while the other 2 were heterozygous and homozygous for the ALG6 variant.

Pittler and a team of researchers at UAB, the University of Pennsylvania, and the State University of New York-University at Buffalo examined data collected over 5 decades for 6 clinical parameters of retinal function and structure in the 11 RP59 patients.

“Quantitative measures of retinal structure and function were performed across five decades of life by evaluating foveal photoreceptor thickness, visual acuity, foveal sensitivity, macular and extramacular rod sensitivity, and kinetic visual field extent,” the researchers wrote in the study. “The ALG6variant, (F304S), was correlated with greater macular cone disease severity and less peripheral rod disease severity.”

The researchers noted in the study that modifier gene polymorphisms may account for a significant portion of phenotypic variation observed in human genetic disease. However, the consequences of the polymorphisms may be counterintuitively complex in terms of rod and cone populations affected in different regions of the retina.2

The study, which was published recently 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.2

“This work represents an early effort in what will become a major part of precision medicine involving big science, artificial intelligence-driven analysis of genetic associations,” Pittler said in the UAB news release. “Overall, these results indicate a potential deficit in macular cone function and simultaneous preservation of peripheral rod health in RP59 patients who co-express a heterozygous phenylalanine-304-to-serine mutation in ALG6.”

Moreover, Pittler pointed out that modifier gene polymorphisms may account for a significant portion of phenotypic variation observed in human genetic disease.

“However, 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,” he said.

Researchers pointed out that in the retina of mammals, rods, and cones are the two types of photoreceptor cells. Cones provide color vision and largely cluster in the small, central foveal and macular region of the retina that allows sharp detailed vision in bright light. Rods function at lower light levels facilitating dim light vision, which is mediated by the more peripheral areas of the retina outside of the macula.

Lead author Elisha Monson, a graduate in the UAB chemistry program, noted in the UAB release that inherited retinal degeneration caused by dehydrodolichyl diphosphate synthase mutation — Effect of an ALG6 modifier variant.

“Taking this project from idea to outcome offered an excellent foundation in modern research and a unique glimpse into the future of precision medicine,” she said in the release. “I am especially grateful to Dr. Pittler and my many mentors in the UAB Department of Chemistry for their generous support.”

Support came from National Institutes of Health grants EY029341 and EY003039-43.

  1. ALG6 acts as a modifier gene in the inherited genetic eye disease retinitis pigmentosa 59. EurekAlert! Accessed March 21, 2024. https://www.eurekalert.org/news-releases/1038478
  2. Monson E, Cideciyan AV, Roman AJ, Sumaroka A, Swider M, Wu V, Viarbitskaya I, Jacobson SG, Fliesler SJ, Pittler SJ. Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation–Effect of an ALG6 Modifier Variant. International Journal of Molecular Sciences. 2024; 25(2):1004. https://doi.org/10.3390/ijms25021004
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