Micale, Lucia and Augello, Bartolomeo and Maffeo, Claudia and Selicorni, Angelo and Zucchetti, Federica and Fusco, Carmela and De Nittis, Pasquelena and Pellico, Maria Teresa and Mandriani, Barbara and Fischetto, Rita and Boccone, Loredana and Silengo, Margherita and Biamino, Elisa and Perria, Chiara and Sotgiu, Stefano and Serra, Gigliola and Lapi, Elisabetta and Neri, Marcella and Ferlini, Alessandra and Cavaliere, Maria Luigia and Chiurazzi, Pietro and Della Monica, Matteo and Scarano, Gioacchino and Faravelli, Francesca and Ferrari, Paola and Mazzanti, Laura and Pilotta, Alba and Patricelli, Maria Grazia and Bedeschi, Maria Francesca and Benedicenti, Francesco and Prontera, Paolo and Toschi, Benedetta and Salviati, Leonardo and Melis, Daniela and Di Battista, Eliana and Vancini, Alessandra and Garavelli, Livia and Zelante, Leopoldo and Merla, Giuseppe (2014) Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Human mutation, Vol. 35 (7), p. 841-850. ISSN 1059-7794. eISSN 1098-1004. Article.
Kabuki syndrome (KS) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. In this study, we performed a mutational screening on 303 Kabuki patients by direct sequencing, MLPA, and quantitative PCR identifying 133 KMT2D, 62 never described before, and four KDM6A mutations, three of them are novel. We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. Furthermore, we demonstrated that the reduction of KMT2D protein level in patients’ lymphoblastoid and skin fibroblast cell lines carrying KMT2D-truncating mutations affects the expression levels of known KMT2D target genes. Finally, we hypothesized that the KS patients may benefit from a readthrough therapy to restore physiological levels of KMT2D and KDM6A proteins. To assess this, we performed a proof-of-principle study on 14 KMT2D and two KDM6A nonsense mutations using specific compounds that mediate translational readthrough and thereby stimulate the re-expression of full-length functional proteins. Our experimental data showed that both KMT2D and KDM6A nonsense mutations displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some Kabuki patients with readthrough inducers.
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