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Harms, F.L. and Girisha, K.M. and Hardigan, A.A. and Kortüm, F. and Shukla, A. and Alawi, M. and Dalal, Ashwin and Brady, L. and Tarnopolsky, M. and Bird, L.M. and Ceulemans, S. and Bebin, M. and Bowling, K.M. and Hiatt, S.M. and Lose, E.J. and Primiano, M. and Chung, W.K. and Juusola, J. and Akdemir, Z.C. and Bainbridge, M. and Charng, W.L. and Drummond-Borg, M. and Eldomery, M.K. and El-Hattab, A.W. and Saleh, M.A.M. and Bézieau, S. and Cogné, B. and Isidor, B. and Küry, S. and Lupski, J.R. and Myers, R.M. and Cooper, G.M. and Kutsche, K. (2017) Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism. The American Journal of Human Genetics, 100 (1). pp. 117-127. ISSN 0002-9297

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From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ∼0.1% of individuals with unexplained neurodevelopmental disorders.

Item Type: Article
Depositing User: Dr P Divakar
Date Deposited: 27 Dec 2016 05:23
Last Modified: 13 Jan 2017 05:27
URI: http://cdfd.sciencecentral.in/id/eprint/762

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