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Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder caused by heterogeneous mutations in the tumor suppressor gene NF1. Neurofibromin, encoded by NF1, 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 NF1NS/+ patients and comprehensively evaluated the efficacy of ataluren treatment. The results demonstrate that hyperactivated GTP‐bound RAS was significantly alleviated in approximately 23% of NF1NS/+ 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 NF1NS/+ 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 NF1NS/+ patients and contributes to expanding insights into NF1 therapy. The therapeutic potential of ataluren for NF1 nonsense mutations was assessed by a comprehensive evaluation of the RAS/MEK/ERK pathway activity in 22 NF1NS/+ patient‐derived fibroblasts. The whole‐transcriptomic profiles between ataluren responders and nonresponders, and further analysis and validation revealed novel biomarkers, AMPD3 and TGFBR3, for monitoring NF1 therapy and highlighted AMPD3 as a new therapeutic target for NF1‐associated diseases.

We examined gene regulation in murine lungs after hind-limb vessel occlusion and reperfusion. A rapid increase of transcript for the AMP deaminase 3 gene (AMPD3) and its enzymatic activity (EC 3.5.4.6) generating inosine monophosphate (IMP) were identified with transcripts located in bronchial and alveolar epithelium. AMP deaminase inhibitor decreased IMP levels and significantly enhanced neutrophil recruitment within lung tissue during reperfusion. In addition, IMP inhibited cytokine-initiated neutrophil infiltration in vivo and selectively attenuated neutrophil rolling by 90% in microvessels. We prepared labeled IMP and demonstrated that IMP specifically binds to neutrophils. IMP also stimulated binding of γ -[35S]thio-GTP, suggesting that IMP is a potent regulator of neutrophils. Taken together, these results elucidate a previously unrecognized mechanism that protects tissues from the potentially deleterious consequences of aberrant neutrophil accumulation. Moreover, they are relevant for new therapeutic approaches to regulate neutrophil responses in inflammation and vascular disease.

Human erythrocyte AMP deaminase (AMPD3) deficiency is a clinically asymptomatic condition characterized by a 50% increase in steady‐state levels of ATP in affected cells. The deficiency in Japanese is associated 75% of the time with the same mutation of R573C, and 25% of the time with other heterogeneous mutations of the AMPD3 gene. The heterozygote frequency was estimated at about 1/30. We previously reported five Japanese individuals who had a complete deficiency of AMPD3. Four were homozygotes for the major mutation of R573C; however, one female did not have the R573C allele. To clarify the mutations in her AMPD3 gene, we analyzed the AMPD3 gene and detected a minor mutation, W450R, derived from the mother and a novel mutation,Q712P, derived from the father. The expression study using AMPD3 cDNA containing both mutations showed that each mutation completely reduced the enzyme activity of AMPD3. As the frequency of carriers heterozygous for these mutations seems to be very low, identifying them may lead to a better understanding of the genetic background of populations in Japan. © 2001 Wiley‐Liss, Inc.