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Series GSE90682 Query DataSets for GSE90682
Status Public on Nov 30, 2016
Title Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia and facial dysmorphism
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Summary From a GeneMatcher-enabled international collaboration, we identified ten individuals with intellectual disability, speech delay, ataxia and facial dysmorphism carrying a deleterious variant in the EBF3 (Early B-cell Factor 3) gene detected by whole-exome sequencing. Five missense, two nonsense, one 9-bp duplication, and one splice-site variant in EBF3 were found; the mutation 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 a mosaic. EBF3 belongs to the early B-cell factor family (also known as Olf, COE, or O/E) and encodes a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicts damaging effects of the five amino acid substitutions on DNA-binding of EBF3. Transient expression of EBF3 mutant proteins in HEK 293T cells revealed mislocalization of all but one mutant in the cytoplasm in addition to nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the CDKN1A reporter gene, and EBF3 mutant proteins were less tightly associated with chromatin as demonstrated by in situ subcellular fractionation experiments. Finally, RNA-seq and ChIP-seq experiments demonstrate that EBF3 acts as a transcriptional regulator and EBF3 mutant protein had reduced genome-wide DNA binding and gene regulatory activity. Our findings demonstrate that variants that disrupt EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay, and are present in ~0.1% of individuals with unexplained neurodevelopmental disorders.
Overall design RNA-sequencing and ChIP-sequencing were performed on SK-N-SH cells stably expressing wild-type EBF3 or mutant (p.P177L) EBF3.
We measured the transcriptome of 3 untransfected Control, 3 EBF3 wild-type expressing and 4 EBF3 p.P177L expressing SK-N-SH replicates, and measured genome-wide binding of two replicates each for EBF3 wild-type and EBF3 p.P177L.
Contributor(s) Harms FL, Girisha KM, Hardigan AA, Myers RM, Cooper GM, Kutsche K
Citation(s) 28017373
Submission date Nov 29, 2016
Last update date May 15, 2019
Contact name Richard M Myers
Organization name HudsonAlpha Institute for Biotechnology
Street address 601 Genome Way
City Huntsville
State/province AL
ZIP/Postal code 35806
Country USA
Platforms (2)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (16)
GSM2410317 SK-N-SH_EBF3_WT_FLAG_Rep_1
GSM2410318 SK-N-SH_EBF3_WT_FLAG_Rep_2
GSM2410319 SK-N-SH_EBF3_P177L_FLAG_Rep_1
BioProject PRJNA355321
SRA SRP094079

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Supplementary file Size Download File type/resource
GSE90682_SK-N-SH_EBF3_RNA-Seq_Count_Table.txt.gz 609.3 Kb (ftp)(http) TXT
GSE90682_SKNSH_EBF3_P177L_FLAG_Peaks_overlap_merge.bed.gz 100.1 Kb (ftp)(http) BED
GSE90682_SKNSH_EBF3_WT_FLAG_Peaks_overlap_merge.bed.gz 562.6 Kb (ftp)(http) BED
GSE90682_SKNSH_P177L_FLAG_1_peaks.narrowPeak.gz 249.1 Kb (ftp)(http) NARROWPEAK
GSE90682_SKNSH_P177L_FLAG_2_peaks.narrowPeak.gz 182.4 Kb (ftp)(http) NARROWPEAK
GSE90682_SKNSH_WT_FLAG_1_peaks.narrowPeak.gz 1.7 Mb (ftp)(http) NARROWPEAK
GSE90682_SKNSH_WT_FLAG_2_peaks.narrowPeak.gz 616.9 Kb (ftp)(http) NARROWPEAK
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