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Expression of mutant JAGGED1 alleles in patients with Alagille syndrome

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Abstract

Heterozygous mutations in JAGGED1 (JAG1), encoding a ligand for Notch receptors, have been identified in patients with Alagille syndrome (AGS). These mutations map to the extracellular and transmembrane domains of JAG1, giving rise in 70% cases to a premature termination codon (PTC). Although haploinsufficiency has been hypothesised as the main mechanism of AGS, a dominant negative effect of truncated forms of Serrate/Jagged has been suggested. Only few studies of the mutant mRNAs and proteins from AGS patients have been performed to elucidate the molecular mechanisms of the disease. To gain insight into the stability of mutant mRNAs, we studied transcripts from five livers and 24 lymphoblastoid cell lines (LCLs) of AGS patients. Mutant JAG1 transcripts were recovered (albeit in different relative amounts) from RNAs with missense mutations (five) or in-frame deletions (two), and from all but two of the 21 with PTCs. In addition, results from LCL RNAs correlated well with results from liver RNAs. Mutant transcripts were also recovered from tissues of a 23-week-old AGS foetus with a PTC mutation. This suggests that most mutant transcripts with PTCs escape nonsense-mediated mRNA decay (NMD) and could lead to the synthesis of soluble forms of JAG1. Production of a truncated protein was indeed observed after transfection of COS cells with a mutant JAG1 cDNA. In conclusion, mutant JAG1 transcripts are present in LCLs, livers and tissues of AGS patients, whatever the mutation type, and mutant proteins can be produced, suggesting a dominant negative effect of some mutant proteins as another molecular mechanism of AGS.

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Acknowledgments

We are very grateful to the patients and their family for participation in this study. We thank Professors Bernard, Bilodeau, Chouraqui, Dabadie, Fellmann, Gottrand, Le Bouedec, Mathieu, Michaud, and Sokal for valuable contribution to this study. J.B. is supported by a fellowship from the French Ministère de la Jeunesse, de l’Education Nationale et de la Recherche (MJENR). This work was supported in part by BQR Univ. Paris XI, and ACI ≪Biologie du développement et physiologie intégrative 2000≫ from MJENR. We thank Pr. Tardieu for the access to the Roche Light Cycler apparatus, and the Infobiogen centre for the free disposal of computing resources.

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Correspondence to Michèle Meunier-Rotival.

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J. Boyer and C. Crosnier contributed equally to this work

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Boyer, J., Crosnier, C., Driancourt, C. et al. Expression of mutant JAGGED1 alleles in patients with Alagille syndrome. Hum Genet 116, 445–453 (2005). https://doi.org/10.1007/s00439-005-1262-7

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  • DOI: https://doi.org/10.1007/s00439-005-1262-7

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