Abstract for presentation at 11th International Congress of Human Genetics

Somatic instability in Friedreich ataxia develops after organogenesis, progresses throughout life, and includes large, age-dependent expansions in dorsal root ganglia

  • Irene De Biase, University of Oklahoma Health Sciences Center, Oklahoma City, United States
  • Dan Endres, University of Central Oklahoma, Edmond, United States
  • Astrid Rasmussen, University of Oklahoma Health Sciences Center, Oklahoma City, United States
  • Sahar Al-Mahdawi, Brunel University, Uxbridge, United Kingdom
  • Antonella Monticelli, Federico II University, Naples, Italy
  • Sergio Cocozza, Federico II University, Naples, Italy
  • Mark Pook, Brunel University, Uxbridge, United Kingdom
  • Sanjay Bidichandani, University of Oklahoma Health Sciences Center, Oklahoma City, United States

    • Friedreich ataxia (FRDA) patients are homozygous for large expansions of a GAA triplet-repeat (GAA-TR) sequence in the FXN gene. Patients develop progressive ataxia in their early teens that eventually renders them non-ambulatory. Neurodegeneration primarily involves the dorsal root ganglia (DRG), followed by spinal cord, and the cerebellum may be variably affected. The reason for this selective neurodegeneration, and the progressive nature of the disease is unclear. We hypothesized that in susceptible tissues the expanded GAA-TR sequence may undergo further, age-dependent expansions. Small-pool PCR (SP-PCR) analysis of ~7000 haploid genomes derived from tissues collected at autopsy from a FRDA patient showed that DRG had a significant tendency for large expansions compared with other tissues (P<0.0001), which was further confirmed in four additional patients. SP-PCR analysis of ~2000 haploid genomes in tissues obtained from an 18-week fetus, homozygous for large expansions, revealed a remarkably low level of instability compared with adults (P<0.0001), indicating that the instability seen in adult-derived tissues develops after organogenesis. Mutation load increased with patient age in a panel of blood DNA derived from donors whose ages ranged from 18-weeks gestation to 43y (7.5%-61.5%; R=0.86; P=0.006). In six autopsies, the frequency of large expansions in DRG, which ranged from 0.5% at 17y to 13.9% at 47y, showed a significant correlation with age (R=0.78; P=0.028). These data indicate that somatic instability in FRDA continues throughout life, and suggests that the primary involvement of DRG may stem, at least in part, from the inordinate frequency and progressive accumulation of large expansions.

    Conference Organiser - ICMS Pty Ltd