The How: Understanding how a gene functions is critical to the development of effective treatments

12.15.22

Research tech, Tonya Moss, loads Western blot gelThe Division of Research at GGC is tasked with asking, and then answering, some of the most challenging questions in biology.

“The questions are often posed to us by our colleagues in the clinical and diagnostic lab divisions when they identify a patient with atypical symptoms or find a novel or unusual genetic variant,” said Rich Steet, PhD, Director of Research at GGC, pictured below. “It then becomes our job to try and figure out how the gene variants in question cause the symptoms that they do. Once we
get to the ‘how this happened’, we have a better sense of the possible ways the condition may be treated.”

Steet and his research team recently collaborated with colleagues at the University of Georgia (UGA), Johns Hopkins School of Medicine, and Children’s Hospital Colorado, on another ‘how’ for two GGC families who have a genetic variant in the gene ALDH18A1. Variants in this gene are known to cause a spectrum of disorders that include skin and neurological findings. ALDH18A1 has also been implicated in several human cancers including breast cancer and melanoma.

In one GGC family, a ten-year-old girl with significant developmental delay, neurologic issues and gastrointestinal concerns, was found to have the new variant. In another family, three siblings who all have the gene variant, exhibit developmental delays, growth issues, loose skin, and gastrointestinal symptoms.

“At this point, all that we can do to treat these children has been to manage some of their symptoms,” said Mike Lyons, MD, Director of Clinical Services at GGC. “If we can understand how the underlying disease is caused by the genetic changes, we have a better chance of intervening at the most basic level and improving their overall health and  development.”

Steet and colleagues used skin cells from one of these four patients to, first of all, confirm that these new variants that were identified were truly disease-causing. “Using cell-based experiments, we were able to show that these genetic variants impact the function of the enzyme encoded by the ALDH18A1 gene,” said Steet, “but that work did not provide any insight about how the genetic change was causing the specific symptoms seen in the patients.” For that, the team explored how the enzyme that is encoded by this gene, P5CS, was altering the metabolic and transcriptional program of the patient’s cells.

Postdoc, Sneha Mokashi, reviews computer data“Our colleagues at UGA looked at the metabolomic profile which is basically a large-scale study of all of the small molecules or metabolites with the cell,” said Steet. “What we found is that the defective enzyme was affecting numerous metabolic pathways that had not been identified in prior studies.”

When the P5CS enzyme is impaired, as it is in these two families, there is a reduction in several metabolites, including a key component of collagen, which Steet said may explain the loose skin findings, and an antioxidant molecule called glutathione which helps protect against oxidative damage and may explain the neurological symptoms.

The researchers also looked at gene expression effects using RNA sequencing, uncovering other sensitive pathways that may contribute to the skin and neurological findings in these children.

“The data from this project point to the involvement of antioxidant responses in the disease process,” said Steet. “We believe that antioxidant supplementation, or drugs that boost the production of antioxidant molecules, may be a possible therapeutic avenue.”

Further studies on cells and animal models to test this hypothesis will be needed before any treatment plan for patients can be considered.

This work was published online in September in advance of print publication in the journal, Human Molecular Genetics.

 

Top photo: Tonya Moss, research technologist and coauthor on the paper, loads a Western blot to analyze the P5CS enzyme encoded by the ALDH18A1 gene.

Bottom photo: Sneha Mokashi, PhD, a postdoctoral associate in the Steet lab and coauthor on the paper, reviews gene expression data for ALDH18A1.

Meet Makayla Gunn

Makayla was diagnosed with Rett Syndrome in April of 2015 at the age of two. At about 18 months, we noticed she had started some repetitive hand motions, and her pediatrician was a little concerned that she did not have many words. She had learned some sign language, and was saying ‘mama’ and ‘dada’, but that was it. Then she suddenly stopped all of that. At her 2 year old check-up, the pediatrician referred us to BabyNet, SC’s early interve...

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