# Defining the impact of Frataxin point mutations on Friedreich's ataxia pathogenesis

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $371,250

## Abstract

Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression
of the mitochondrial protein frataxin (FXN). Frataxin is translated as a 210 amino acid (aa) precursor (FXN-P)
that is imported into the mitochondrial matrix where it undergoes sequential cleavage steps, producing a 168 aa
intermediate (FXN-I) and the mature isoform of 129 aa (FXN-M). Frataxin participates in iron-sulfur cluster (ISC)
biosynthesis in the mitochondria, and many of the overt FRDA phenotypes result from deficient activity of ISC-
containing enzymes. Currently, there is no cure for this debilitating disease. Most FRDA patients are
homozygous for large expansions of GAA triplet repeat sequences in intron 1 of the FXN gene, while a subset
of patients are compound heterozygotes with an expanded GAA repeat tract in one FXN allele and a missense
or nonsense mutation in the other. Homozygous and compound heterozygous mutant genotypes both result in
reduced levels of FXN-M protein when compared with healthy controls. The most prevalent missense mutation
changes a glycine to valine at position 130 (G130V). FRDA G130V patients exhibit different clinical features than
patients harboring homozygous GAA expansions, including lower limb spasticity rather than ataxia, preserved
sensory responses, spared speech and upper limb functions, and slower disease progression. Paradoxically,
substantially less FXN-M protein is detectable in G130V patient samples than in patient samples harboring two
expanded alleles. Our preliminary data revealed that normal mitochondrial maturation processing of the FXN
protein is perturbed by the G130V mutation, suggesting functional importance of an intermediate isoform
(G130V-I). We hypothesize that the G130V mutation impairs FXN mitochondrial maturation processing and/or
destabilizes the mature isoform. The unprocessed FXN-G130V-I isoform is functional and partially compensates
for the substantial reduction of FXN-M, thus slowing disease progression and contributing to the distinct
symptoms of FRDA G130V patients. To address these hypotheses, we will use novel cellular and mouse models
of FRDA G130V. First, we will define the structural and functional properties of the FXN-G130V-I isoform to test
whether this mutation confers a change of function that contributes to the atypical clinical presentation of FRDA
G130V patients. Subsequently, we will determine mechanisms governing steady state levels and maturation
processing of FXN-G130V in iPSC-derived cortical and sensory neurons. Finally, using FRDA patient-derived
neuronal models as well as our novel Fxn G127V mouse model, we will define molecular mechanisms underlying
the unique clinical presentation of FRDA G130V patients. Results of the proposed studies will have a broad
impact on therapy development for all FRDA patients.

## Key facts

- **NIH application ID:** 10181593
- **Project number:** 1R01NS121038-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Marek Napierala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $371,250
- **Award type:** 1
- **Project period:** 2021-03-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10181593

## Citation

> US National Institutes of Health, RePORTER application 10181593, Defining the impact of Frataxin point mutations on Friedreich's ataxia pathogenesis (1R01NS121038-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10181593. Licensed CC0.

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