Activity of 5 genes tied to immune system, cell maturity affected in FA
Study finds 398 genes, in total, altered between sisters with and without disease
A genetic analysis of connective tissue cells from a woman with late-onset Friedreich’s ataxia (FA) and her younger sister, who did not have the disease, found differences in the activity levels of almost 400 genes in the affected sister, according to a recent study.
Genes with the most altered activity in this woman were related to the immune system and cell development in the brain and heart.
The sister who was asymptomatic — exhibiting no FA symptoms — nevertheless had lower than normal levels of frataxin, the protein affected by disease-causing mutations.
“We tried to go deeper into the mechanisms differentiating the two sisters by performing RNA … analysis,” the researchers, working with a family in their home country of Italy, wrote. “The ultimate goal was to identify genes and/or pathways that are differently involved in the clinical manifestation of [FA].”
Older sister with late-onset FA had higher number GAA repeats
The study, “Differential Gene Expression in Late-Onset Friedreich Ataxia: A Comparative Transcriptomic Analysis Between Symptomatic and Asymptomatic Sisters,” was published in the International Journal of Molecular Sciences.
Mutations in the FXN gene, which contains the instructions for producing the protein frataxin, a mitochondrial protein important for cellular energy, cause Friedreich’s ataxia. The most common mutation is excessive repeats of three nucleotides, or DNA building blocks — one guanine (G) and two adenine (A). In healthy people this sequence is repeated up to 33 times, but people with FA can have more than 1,000 repeats.
The two women underwent a detailed genetic analysis because both had low levels of frataxin in connective tissue cells, known as fibroblasts. Connective tissue, as its name implies, connects and supports all other tissues in the body.
The older woman, age 43, was diagnosed with late-onset FA after developing progressive spastic ataxia, or poor muscle control associated with clumsy movements and spasticity, starting at the age of 35. Her younger sister, age 36, was asymptomatic during four years of study follow-up.
The affected sister had inherited two mutated FXN gene copies with extended GAA repeats.
The younger woman had inherited one gene copy with extended GAA repeats, though fewer than her sister. Her other FXN gene copy had a rare mutation, with 66 to 67 repeats of GAAGGA.
Activity of 398 genes differed, with 2 most altered tied to immune system
Fibroblasts were obtained from skin biopsies of each woman. For the genetic analysis, the researchers used a technique known as RNA sequencing, which analyzes the cell’s RNA, the intermediate molecules formed when the body uses the instructions encoded in DNA to make proteins.
RNA sequencing revealed 398 genes with differing activity between the two sisters. In the woman with FA, 212 genes had increased activity and 186 genes had decreased activity.
Focusing on the five genes with the most notably altered activity, TLR4 plays a role in promoting inflammation by stimulating the immune system. TLR4, the protein coded by the TLR4 gene, is known to be involved in several neurodegenerative diseases, including Parkinson’s and amyotrophic lateral sclerosis.
IL20RB, another gene with higher activity in the sister with FA, codes for a receptor protein of the same name used in cell communication, which is also known to promote immune responses and contribute to inflammatory diseases like psoriasis and rheumatoid arthritis.
“To the best of our knowledge, so far, no research study has described any direct interaction between TLR4 and IL-20RB, but we cannot rule out the idea that both signaling pathways might be implicated simultaneously in the disease, contributing to the exacerbation of the disease’s activity,” the scientists noted.
3 other highly affected genes have roles in cell maturation
“The evidence supports a strong involvement of the neuro-inflammatory mechanism” in FA, they added. “Our results, comparing a symptomatic sister with her asymptomatic sister, may help to highlight the importance of inflammation in the development of clinical symptoms.”
However, it is unclear whether inflammation, particularly in the brain, causes or results from disease progression.
“The role of neuro-inflammation, as a cause or consequence of the disease onset and progression, still needs to be defined,” the researchers wrote.
Three other genes with the greatest differences in activity — SLITRK5, GRIN2A, and TCF21 — were related to development. SLITRK5 had higher activity in the affected sister, whereas the opposite was seen in her other two genes. SLITRK5 and GRIN2A are both related to nerve cell maturation, while TCF21 has been linked to the process wherein heart cells reach their specialized form and function. The researchers suggested that the differences in activity seen in these developmental genes could contribute to the neurological and heart-related symptoms often experienced by FA patients.
“Our study is the first to evidence an abnormal expression [activity] of inflammatory (IL-20R and TLR4) and developmental genes (SLITRK5, GRIN2A, and TCF21) in [FA],” the team concluded.
