The nonsense mutation stop+4 model correlates with motor changes in Duchenne muscular dystrophy

on behalf on the International DMD group, C. Brogna, G. Coratti, R. Rossi, M. Neri, S. Messina, A.D. Amico, C. Bruno, S. Lucibello, G. Vita, A. Berardinelli, F. Magri, F. Ricci, M. Pedemonte, T. Mongini, R. Battini, L. Bello, E. Pegoraro, G. Baranello, L. PolitanoG.P. Comi, V.A. Sansone, E. Albamonte, A. Donati, E. Bertini, N. Goemans, S. Previtali, F. Bovis, M. Pane, A. Ferlini, E. Mercuri

Research output: Contribution to journalArticlepeer-review

Abstract

The aim was to assess 3-year longitudinal data using 6MWT in 26 ambulant boys affected by DMD carrying nonsense mutations and to compare their results to other small mutations. We also wished to establish, within the nonsense mutations group, patterns of change according to several variables. Patients with nonsense mutations were categorized according to the stop codon type newly created by the mutation and also including the adjacent 5′ (upstream) and 3′ (downstream) nucleotides. No significant difference was found between nonsense mutations and other small mutations (p > 0.05) on the 6MWT. Within the nonsense mutations group, there was no difference in 6MWT when the patients were subdivided according to: Type of stop codon, frame status of exons involved, protein domain affected. In contrast, there was a difference when the stop codon together with the 3′ adjacent nucleotide (“stop+4 model”) was considered (p < 0.05) with patients with stop codon TGA and 3′ adjacent nucleotide G (TGAG) having a more rapid decline. Our finding suggest that the stop+4 model may help in predicting functional changes. This data will be useful at the time of interpreting the long term follow up of patients treated with Ataluren that are becoming increasingly available.

Original languageEnglish
Pages (from-to)479-488
Number of pages10
JournalNeuromuscular Disorders
Volume31
Issue number6
DOIs
Publication statusPublished - 2021

Keywords

  • Duchenne
  • Nonsense mutation
  • Stop+4 model
  • deflazacort
  • dystrophin
  • nucleotide
  • Article
  • child
  • cohort analysis
  • controlled study
  • Duchenne muscular dystrophy
  • follow up
  • frameshift mutation
  • gene deletion
  • gene duplication
  • genetic association
  • genotype phenotype correlation
  • human
  • infant
  • intellectual impairment
  • longitudinal study
  • major clinical study
  • male
  • missense mutation
  • motor performance
  • mutational analysis
  • nonsense mutation
  • preschool child
  • problem behavior
  • protein domain
  • RNA splicing
  • six minute walk test
  • stop codon

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