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Molecular Analysis, Pathogenic Mechanisms, and Readthrough Therapy on a Large Cohort of K abuki Syndrome Patients
Author(s) -
Micale Lucia,
Augello Bartolomeo,
Maffeo Claudia,
Selicorni Angelo,
Zucchetti Federica,
Fusco Carmela,
De Nittis Pasquelena,
Pellico Maria Teresa,
Mandriani Barbara,
Fischetto Rita,
Boccone Loredana,
Silengo Margherita,
Biamino Elisa,
Perria Chiara,
Sotgiu Stefano,
Serra Gigliola,
Lapi Elisabetta,
Neri Marcella,
Ferlini Alessandra,
Cavaliere Maria Luigia,
Chiurazzi Pietro,
Monica Matteo Della,
Scarano Gioacchino,
Faravelli Francesca,
Ferrari Paola,
Mazzanti Laura,
Pilotta Alba,
Patricelli Maria Grazia,
Bedeschi Maria Francesca,
Benedicenti Francesco,
Prontera Paolo,
Toschi Benedetta,
Salviati Leonardo,
Melis Daniela,
Di Battista Eliana,
Vancini Alessandra,
Garavelli Livia,
Zelante Leopoldo,
Merla Giuseppe
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22547
Subject(s) - kabuki syndrome , biology , haploinsufficiency , nonsense mutation , genetics , gene , frameshift mutation , mutation , phenotype , missense mutation
K abuki syndrome ( KS ) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT 2 D / MLL 2 and KDM 6 A / UTX genes. In this study, we performed a mutational screening on 303 K abuki patients by direct sequencing, MLPA , and quantitative PCR identifying 133 KMT 2 D , 62 never described before, and four KDM 6 A mutations, three of them are novel. We found that a number of KMT 2 D truncating mutations result in m RNA degradation through the nonsense‐mediated m RNA decay, contributing to protein haploinsufficiency. Furthermore, we demonstrated that the reduction of KMT 2 D protein level in patients’ lymphoblastoid and skin fibroblast cell lines carrying KMT 2 D ‐truncating mutations affects the expression levels of known KMT 2 D target genes. Finally, we hypothesized that the KS patients may benefit from a readthrough therapy to restore physiological levels of KMT 2 D and KDM 6 A proteins. To assess this, we performed a proof‐of‐principle study on 14 KMT 2 D and two KDM 6 A 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 KMT 2 D and KDM 6 A nonsense mutations displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some K abuki patients with readthrough inducers.