PTC124 improves readthrough and increases enzymatic activity of the CPT1A R160X nonsense mutation

J Inherit Metab Dis. 2011 Apr;34(2):443-7. doi: 10.1007/s10545-010-9265-5. Epub 2011 Jan 21.

Abstract

Deficiency of carnitine palmitoyltransferase 1A (CPT1A) results in impaired hepatic long-chain fatty acid oxidation and ketogenesis. We have previously described a patient with a severe CPT1A phenotype who is homozygous for the nonsense mutation 478 C > T (R160X). It has been known for some time that gentamicin can promote readthrough of nonsense codons. Recently, a new compound (PTC124) with less clinical toxicity than gentamicin has been indicated as a therapy for patients with nonsense mutations for multiple genetic diseases. The study is designed to investigate whether PTC124 can promote readthrough of the R160X CPT1A mutation and increase normal sized CPT1 protein expression and activity in the patient's skin fibroblasts. Our study demonstrated that after both PTC 124 and gentamicin treatment, there was an increase in CPT1 activity in patient fibroblasts to levels that are similar to that of the mild Inuit P479L variant. Our results provide additional evidence for proof of principle that PTC124 is a potential therapeutic agent for treating patients with any genetic condition that results from a nonsense mutation.

Publication types

  • Case Reports

MeSH terms

  • Carnitine O-Palmitoyltransferase / genetics*
  • Child, Preschool
  • Codon
  • Codon, Nonsense*
  • Fatty Acids / chemistry
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gentamicins / pharmacology
  • Homozygote
  • Humans
  • Hyperammonemia / genetics
  • Hypoglycemia / genetics
  • Ketones / metabolism
  • Liver Diseases / genetics
  • Mutation
  • Oxadiazoles / chemistry*
  • Oxygen / chemistry
  • Phenotype
  • Skin / metabolism

Substances

  • Codon
  • Codon, Nonsense
  • Fatty Acids
  • Gentamicins
  • Ketones
  • Oxadiazoles
  • Carnitine O-Palmitoyltransferase
  • ataluren
  • Oxygen