Ataluren‐Induced Functional Restoration of Neurofibromin in Fibroblasts From Neurofibromatosis Type 1 Patients With Nonsense Mutations

Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder caused by heterogeneous mutations in the tumor suppressor gene <i>NF1</i>. Neurofibromin, encoded by <i>NF1</i>, predominantly acts as a negative regulator of the RAS-MEK signaling pathway. Up to 30% of NF1 patients harbor nonsense mutations (NS) that introduce premature termination codons (PTCs). Ataluren is a well-characterized small molecule that acts as a nonsense suppressor by enhancing the ribosomal readthrough of PTCs. Here, we isolated primary fibroblasts from 22 Korean <i>NF1^NS/+</i> patients and comprehensively evaluated the efficacy of ataluren treatment. The results demonstrate that hyperactivated GTP-bound RAS was significantly alleviated in approximately 23% of <i>NF1^NS/+</i> fibroblasts, and the cellular levels of phosphorylated ERK also decreased in approximately 24% after ataluren treatment. Through transcriptome-wide profiling based on ataluren responsiveness, we analyzed a subset of genes in ataluren-treated <i>NF1^NS/+</i> fibroblasts whose expression was significantly altered in ataluren-responsive cells, but not in nonresponsive cells. Furthermore, both AMPD3 and TGFBR3 were notably identified as feasible biomarkers for monitoring functional neurofibromin. Interestingly, AMPD3 can be an effective therapeutic target for NF1-associated diseases. Together, our study suggests that ataluren can be considered a therapeutic agent for some <i>NF1^NS/+</i> patients and contributes to expanding insights into NF1 therapy.