Large Interruptions of GAA Repeat Expansion Mutations in Friedreich Ataxia Are Very Rare.

Sahar Al-Mahdawi,Francesca Cavalcanti,Paola Giunti,Valentina La Cognata,Aurelien Bayot,Sebastiano Cavallaro,Mark A Pook,Heather Ging

doi:10.3389/fncel.2018.00443

Abstract

Friedreich ataxia is a multi-system autosomal recessive inherited disorder primarily caused by homozygous GAA repeat expansion mutations within intron 1 of the frataxin gene. The resulting deficiency of frataxin protein leads to progressive mitochondrial dysfunction, oxidative stress, and cell death, with the main affected sites being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum. The GAA repeat expansions may be pure (GAA)n in sequence or may be interrupted with regions of non-GAA sequence. To our knowledge, there has been no large-scale study of FRDA patient DNA samples to determine the frequency of large interruptions in GAA repeat expansions. Therefore, we have investigated a panel of 245 Friedreich ataxia patient and carrier DNA samples using GAA repeat PCR amplification and MboII restriction enzyme digestion. We demonstrate that the vast majority (97.8%) of Friedreich ataxia GAA repeat expansion samples do not contain significant sequence changes that would result in abnormal MboII digestion profiles, indicating that they are primarily pure GAA repeats. These results show for the first time that large interruptions in the GAA repeats are very rare.

Highlights

Friedreich ataxia (FRDA) is a multi-system autosomal recessive inherited disorder characterized by neurological features of ataxia, dysarthria, weakness, ocular fixation instability, deep sensory loss, and visual and hearing impairment, together with non-neurological features such as hypertrophic cardiomyopathy, diabetes mellitus, kyphoscoliosis, and foot deformities (Reetz et al, 2015)
We find that the vast majority (97.8%) of FRDA patient DNA samples do not contain substantial sequence changes that would result in abnormal MboII digestion profiles, indicating that they are primarily pure GAA repeats
From our starting cohort of 245 samples, we identified 199 homozygous GAA repeat expansion FRDA patient samples for which data were available on age of onset in addition to both GAA repeat allele sizes (Supplementary Table S1)

Summary

Introduction

Friedreich ataxia (FRDA) is a multi-system autosomal recessive inherited disorder characterized by neurological features of ataxia, dysarthria, weakness, ocular fixation instability, deep sensory loss, and visual and hearing impairment, together with non-neurological features such as hypertrophic cardiomyopathy, diabetes mellitus, kyphoscoliosis, and foot deformities (Reetz et al, 2015). The GAA repeat size accounts for only approximately 36% to 56% of the variation in age of onset (Durr et al, 1996; Filla et al, 1996; Reetz et al, 2015). This suggests that there are other contributory mechanisms such as somatic mosaicism, interruptions in the GAA repeat sequence, and other modifying genes or environmental factors, which influence age of onset (Filla et al, 1996; Pandolfo, 2009; Reetz et al, 2015). Patients with late-onset disease have a milder phenotype and slower disease progression (Durr et al, 1996)

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