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Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism
- Source :
- Web of Science, American journal of human genetics, vol 100, iss 1
-
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 insitu 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.
- Subjects :
- Models, Molecular
0301 basic medicine
Male
Transcription, Genetic
Developmental Disabilities
Mutant
Medical and Health Sciences
Transactivation
Genes, Reporter
Models
Gene duplication
Missense mutation
2.1 Biological and endogenous factors
Exome
Aetiology
Child
Genetics (clinical)
transcription factor
Regulation of gene expression
Genetics
Pediatric
Genetics & Heredity
Mosaicism
Syndrome
Biological Sciences
Chromatin
developmental delay
Protein Transport
Child, Preschool
Female
medicine.symptom
Transcription
Biotechnology
Adult
Cyclin-Dependent Kinase Inhibitor p21
Ataxia
Adolescent
Intellectual and Developmental Disabilities (IDD)
Biology
03 medical and health sciences
Genetic
Report
Intellectual Disability
medicine
Humans
Language Development Disorders
Preschool
Transcription factor
Reporter
EBF3
Human Genome
Molecular
Molecular biology
de novo mutation
Brain Disorders
030104 developmental biology
HEK293 Cells
Amino Acid Substitution
Gene Expression Regulation
Genes
Neurodevelopmental Disorders
Face
Mutation
Generic health relevance
gene regulation
Transcription Factors
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Web of Science, American journal of human genetics, vol 100, iss 1
- Accession number :
- edsair.doi.dedup.....dd7a32a1df5bc033f6e893a9ba6ec360