@article {338, title = {Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {117-127}, abstract = {

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.

}, keywords = {Adolescent, 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}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.012}, author = {Harms, Frederike Leonie and Girisha, Katta M and Hardigan, Andrew A and Kort{\"u}m, Fanny and Shukla, Anju and Alawi, Malik and Dalal, Ashwin and Brady, Lauren and Tarnopolsky, Mark and Bird, Lynne M and Ceulemans, Sophia and Bebin, Martina and Bowling, Kevin M and Hiatt, Susan M and Lose, Edward J and Primiano, Michelle and Chung, Wendy K and Juusola, Jane and Akdemir, Zeynep C and Bainbridge, Matthew and Charng, Wu-Lin and Drummond-Borg, Margaret and Eldomery, Mohammad K and El-Hattab, Ayman W and Saleh, Mohammed A M and B{\'e}zieau, St{\'e}phane and Cogn{\'e}, Benjamin and Isidor, Bertrand and K{\"u}ry, S{\'e}bastien and Lupski, James R and Myers, Richard M and Cooper, Gregory M and Kutsche, Kerstin} }