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Dissecting KMT2D missense mutations in Kabuki syndrome patients.

  • Cocciadiferro D Division of Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
  • Augello B Division of Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
  • De Nittis P Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
  • Zhang J Department of Pathology and Cell Biology, Institute for Cancer Genetics, Columbia University, New York, NY, USA.
  • Mandriani B Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy.
  • Malerba N Division of Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
  • Squeo GM Division of Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
  • Romano A Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
  • Piccinni B Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.
  • Verri T Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.
  • Micale L Division of Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
  • Pasqualucci L Department of Pathology and Cell Biology, Institute for Cancer Genetics, Columbia University, New York, NY, USA.
  • Merla G Division of Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
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  • 2018-08-15
Published in:
  • Human molecular genetics. - 2018
Abnormalities, Multiple
Computer Simulation
DNA-Binding Proteins
Face
Hematologic Diseases
Histone Demethylases
Humans
Models, Molecular
Mutation
Mutation, Missense
Neoplasm Proteins
Nuclear Proteins
Protein Conformation
Sequence Analysis, Protein
Vestibular Diseases
English Kabuki syndrome is a rare autosomal dominant condition characterized by facial features, various organs malformations, postnatal growth deficiency and intellectual disability. The discovery of frequent germline mutations in the histone methyltransferase KMT2D and the demethylase KDM6A revealed a causative role for histone modifiers in this disease. However, the role of missense mutations has remained unexplored. Here, we expanded the mutation spectrum of KMT2D and KDM6A in KS by identifying 37 new KMT2D sequence variants. Moreover, we functionally dissected 14 KMT2D missense variants, by investigating their impact on the protein enzymatic activity and the binding to members of the WRAD complex. We demonstrate impaired H3K4 methyltransferase activity in 9 of the 14 mutant alleles and show that this reduced activity is due in part to disruption of protein complex formation. These findings have relevant implications for diagnostic and counseling purposes in this disease.
Language
  • English
Open access status
green
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Persistent URL
https://sonar.ch/global/documents/150692
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