title: In vitro readthrough of termination codons by gentamycin in the Stüve-Wiedemann Syndrome.
abstract: The Stüve-Wiedemann Syndrome (SWS) is a frequently lethal chondrodysplasia caused by null mutations in the leukemia inhibitory factor receptor gene (LIFR) responsible for an impaired activation of the JAK-STAT pathway after LIF stimulation. Most LIFR mutations are nonsense mutations, thus prompting us to investigate the impact of aminoglycosides on the readthrough of premature termination codons (PTCs). Culturing skin fibroblasts from three SWS patients and controls for 48 h in the presence of gentamycin (200-500 microg/ml) partially restored the JAK-STAT3 pathway when stimulated by LIF. Consistently, quantitative RT-PCR analysis showed that gentamycin stabilized LIFR mRNAs carrying UGA premature termination codons. We conclude that high gentamycin concentrations can partially restore functional LIFR protein synthesis in vitro, prompting us to investigate PTC readthrough using less toxic and more efficient drugs in this presently untreatable lethal condition.
authors: Département de Génétique, Université Paris Descartes, INSERM U781, Assistance Publique-Hôitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France.
authors: Samuel
authors: S
authors: Bellais
authors: Carine
authors: C
authors: Le Goff
authors: Nathalie
authors: N
authors: Dagoneau
authors: Arnold
authors: A
authors: Munnich
authors: Valérie
authors: V
authors: Cormier-Daire
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics*; D018388:Codon, Terminator / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005839:Gentamicins / Q000494:pharmacology*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000235:genetics; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013577:Syndrome
chemical_list: D018388:Codon, Terminator; D005839:Gentamicins; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D050791:STAT Transcription Factors; D053612:Janus Kinases