α-l-Iduronidase Premature Stop Codons and Potential Read-Through in Mucopolysaccharidosis Type I Patients

Effect of Readthrough Treatment in Fibroblasts of Patients Affected by Lysosomal Diseases Caused by Premature Termination Codons

“…Therefore, it seems worthwhile to perform preliminary approaches with already proven readthrough compounds, such as gentamcin or PTC124, to select responsive mutations before starting a readthrough screening with selected libraries or with other compounds. Surprisingly, and similarly to previous observations with other LSD [14,15,23], we found a significant and unexplained reduction of residual enzymatic activity upon gentamicin treatment in fibroblasts from patient 7 (Fabry disease). This reduction cannot be due to cell toxicity as cell viability was normal.…”

“…In our study, we focused on nonsense or frameshift mutations leading to PTC resulting in an almost complete absence of particular key proteins involved in lysosomal function and cell homeostasis maintenance. Preclinical studies with gentamicin or PTC124 had succeeded by enhancing stop codon readthrough and were able to be used as therapeutic agents for genetic diseases [9][10][11][12][13][14][15][16][17][18][36][37][38][39][40][41][42]. PTC124 has been successfully extended into clinical trials [18,43], although preliminary results are not clear for Duchenne muscular dystrophy [44].…”

“…Although major progress has been made in gene therapy, it is still far from achieving real clinical application. In the last few years, other potential strategies such as pharmacological chaperones [8], or the suppression of pathogenic nonsense mutations through the induction of translational readthrough have emerged [2,[9][10][11][12][13][14][15][16][17][18]. To this effect, aminoglycoside antibiotics such as gentamicin [16,17], and small molecules such as PTC124 [18] and NB84 [19], have been described to induce PTC readthrough, eluding the NMD mechanism and allowing the formation of stable mRNAs encoding for full-length mutant, but probably still quite active, proteins [20,21].…”

Experimental verification of the Kruskal-Shafranov stability limit in line-tied partial-toroidal plasmas

“…These arched structures intersect the dense photosphere at footpoints that are believed to be anchored or "line-tied" in place. 1 Energetic events such as coronal mass ejections (CMEs) 2 are often regarded as a consequence of instability and/or loss of equilibrium in one of these partial toroidal structures. 1,[3][4][5][6][7] One potential CME trigger mechanism is the ideal external kink instability (see, e.g., Török and Kliem 8 ).…”

“…1 Energetic events such as coronal mass ejections (CMEs) 2 are often regarded as a consequence of instability and/or loss of equilibrium in one of these partial toroidal structures. 1,[3][4][5][6][7] One potential CME trigger mechanism is the ideal external kink instability (see, e.g., Török and Kliem 8 ). Despite rapid progress in observational capabilities, the lack of detailed magnetic measurements in crucial areas of the corona has prevented the conclusive study of kink stability in coronal magnetic structures.…”