{
  "abstract": "Background Nonsense variants, which generate premature termination codons (PTC), in ABHD12 gene represent almost one third of the reported variants in PHARC syndrome. ABHD12 protein is responsible for the breakdown of lyso-phosphatidylserines in the central nervous system, and lipid dysregulation has been highlighted as the central pathophysiology mechanism in PHARC. Translational readthrough-inducing drugs (TRIDs) can enhance the read-through of PTC leading to expression of full-length ABHD12 protein. We aimed to assess the efficacy of two TRIDs (amlexanox and ataluren/PTC124); and to generate a human iPSC-RPE line from the patient‘s fibroblasts.Methods Fibroblasts from one patient harbouring a homozygous nonsense variant in ABHD12 c.193C>T, p.(Arg65*) were isolated, cultured and dosed with TRIDs. Gene expression was assessed by qPCR. ABHD12 presence was detected by immunoblotting. Lipidomic analysis was performed by LC-MS. iPSC-RPE line was generated from the PHARC patient’s fibroblasts by reprogramming with episomal plasmids and subsequent differentiation.Results PHARC fibroblasts only express the alternative splicing ABHD12-b isoform. At protein level, amlexanox treatment led to an increase in the ABHD12-b isoform production in PHARC fibroblasts. At metabolomic level, PHARC patient cells exhibited alterations in glycerophospholipids and sphingolipids that were restored by amlexanox dosing. No effect was observed in PHARC cells treated with ataluren/PTC124.Conclusions A proportion of ABHD12 transcripts are escaping the nonsense mediated decay in PHARC cells, a favourable prognostic indicator of readthrough potential. The restoring effect on lipid dysregulation in PHARC fibroblasts by amlexanox, suggests TRIDs could be a potential therapeutic option for individuals carrying in-frame nonsense variants in ABHD12 gene.",
  "authors": [
    {
      "affiliations": [
        "UCL Institute of Ophthalmology, London EC1V 9EL, UK"
      ],
      "name": "Sara Romero-Vázquez"
    },
    {
      "affiliations": [
        "UCL Institute of Ophthalmology, London EC1V 9EL, UK",
        "The Francis Crick Institute, London NW1 1AT, UK",
        "Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK"
      ],
      "name": "Mariya Moosajee"
    }
  ],
  "title": "#ECR-Poster-04 Targeting an in-frame nonsense variant in ABHD12 gene causing PHARC syndrome with translational read-through-inducing drugs (TRIDs)",
  "uid": "5793ab5b-e621-5395-852d-f3640e245d9e"
}