Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism.

TitleMutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism.
Publication TypeJournal Article
Year of Publication2017
AuthorsHarms, FLeonie, Girisha, KM, Hardigan, AA, Kortüm, F, Shukla, A, Alawi, M, Dalal, A, Brady, L, Tarnopolsky, M, Bird, LM, Ceulemans, S, Bebin, M, Bowling, KM, Hiatt, SM, Lose, EJ, Primiano, M, Chung, WK, Juusola, J, Akdemir, ZC, Bainbridge, M, Charng, W-L, Drummond-Borg, M, Eldomery, MK, El-Hattab, AW, Saleh, MAM, Bézieau, S, Cogné, B, Isidor, B, Küry, S, Lupski, JR, Myers, RM, Cooper, GM, Kutsche, K
JournalAm J Hum Genet
Date Published2017 Jan 05
KeywordsAdolescent, Adult, Amino Acid Substitution, Ataxia, Child, Child, Preschool, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, Developmental Disabilities, Exome, Face, Female, Gene Expression Regulation, Genes, Reporter, HEK293 Cells, Humans, Intellectual Disability, Language Development Disorders, Male, Models, Molecular, Mosaicism, Mutation, Neurodevelopmental Disorders, Protein Transport, Syndrome, Transcription Factors, Transcription, Genetic

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.

Alternate JournalAm J Hum Genet
PubMed ID28017373
PubMed Central IDPMC5223027
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
R01 CA197139 / CA / NCI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R21 NS094047 / NS / NINDS NIH HHS / United States
T32 GM008361 / GM / NIGMS NIH HHS / United States
UM1 HG007301 / HG / NHGRI NIH HHS / United States

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