New Results
Mutations in EBF3 disturb transcriptional profiles and underlie a novel syndrome of intellectual disability, ataxia and facial dysmorphism
Frederike Leonie Harms, Katta Mohan Girisha, View ORCID ProfileAndrew A. Hardigan, Fanny Kortüm, Anju Shukla, Malik Alawi, Ashwin Dalal, Lauren Brady, Mark Tarnopolsky, Lynne M. Bird, Sophia Ceulemans, Martina Bebin, Kevin M. Bowling, Susan M. Hiatt, Edward J. Lose, Michelle Primiano, Wendy K. Chung, Jane Juusola, Zeynep C. Akdemir, Matthew Bainbridge, Wu-Lin Charng, Margaret Drummond-Borg, Mohammad K. Eldomery, Ayman W. El-Hattab, Mohammed A.M. Saleh, Stéphane Beziéau, Benjamin Cogné, Bertrand Isidor, Sébastien Küry, James R. Lupski, Richard M. Myers, Gregory M. Cooper, Kerstin Kutsche
doi: https://doi.org/10.1101/067454
Frederike Leonie Harms
1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Katta Mohan Girisha
2Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India
Andrew A. Hardigan
3HudsonAlpha Institute for Biotechnology, Huntsville, AL USA
4Department of Genetics, University of Alabama at Birmingham, AL USA
Fanny Kortüm
1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Anju Shukla
2Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India
Malik Alawi
5University Medical Center Hamburg-Eppendorf, Bioinformatics Service Facility, Hamburg, Germany
6Center for Bioinformatics, University of Hamburg, Hamburg, Germany
7Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Virus Genomics, Hamburg, Germany
Ashwin Dalal
8Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India
Lauren Brady
9Department of Pediatrics, McMaster University Medical Center, Hamilton, Ontario, L8N 3Z5, Canada
Mark Tarnopolsky
9Department of Pediatrics, McMaster University Medical Center, Hamilton, Ontario, L8N 3Z5, Canada
Lynne M. Bird
10Department of Pediatrics, University of California, San Diego, CA 92123, USA
11Division of Genetics/Dysmorphology, Rady Children’s Hospital San Diego, San Diego, CA 92123, USA
Sophia Ceulemans
11Division of Genetics/Dysmorphology, Rady Children’s Hospital San Diego, San Diego, CA 92123, USA
Martina Bebin
12Department of Neurology, University of Alabama at Birmingham, Birmingham, AL USA
Kevin M. Bowling
3HudsonAlpha Institute for Biotechnology, Huntsville, AL USA
Susan M. Hiatt
3HudsonAlpha Institute for Biotechnology, Huntsville, AL USA
Edward J. Lose
13Department of Genetics, University of Alabama at Birmingham, Birmingham, AL USA
Michelle Primiano
14Department of Pediatrics and Medicine, Columbia University, New York NY 10032, USA
Wendy K. Chung
14Department of Pediatrics and Medicine, Columbia University, New York NY 10032, USA
Jane Juusola
15GeneDx, Gaithersburg, MD 20877, USA
Zeynep C. Akdemir
16Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Matthew Bainbridge
17Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA
Wu-Lin Charng
16Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Margaret Drummond-Borg
18Cook Children’s Genetic Clinic, Fort Worth, Texas, USA
Mohammad K. Eldomery
16Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Ayman W. El-Hattab
19Division of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates
Mohammed A.M. Saleh
20Section of Medical Genetics, Children’s Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Stéphane Beziéau
21CHU Nantes, Service de Génétique Médicale, Nantes CEDEX 1, France
Benjamin Cogné
21CHU Nantes, Service de Génétique Médicale, Nantes CEDEX 1, France
Bertrand Isidor
21CHU Nantes, Service de Génétique Médicale, Nantes CEDEX 1, France
22INSERM, UMR-S 957, Nantes, France
Sébastien Küry
21CHU Nantes, Service de Génétique Médicale, Nantes CEDEX 1, France
James R. Lupski
16Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Richard M. Myers
3HudsonAlpha Institute for Biotechnology, Huntsville, AL USA
Gregory M. Cooper
3HudsonAlpha Institute for Biotechnology, Huntsville, AL USA
Kerstin Kutsche
1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Abstract
From a GeneMatcher-enabled international collaboration, we identified ten individuals with intellectual disability, speech delay, ataxia and facial dysmorphism and a mutation in EBF3, encoding a transcription factor required for neuronal differentiation. Structural assessments, transactivation assays, in situ fractionation, RNA-seq and ChlP-seq experiments collectively show that the mutations are deleterious and impair EBF3 transcriptional regulation. These findings demonstrate that EBF3-mediated dysregulation of gene expression has profound effects on neuronal development in humans.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Posted August 03, 2016.
Mutations in EBF3 disturb transcriptional profiles and underlie a novel syndrome of intellectual disability, ataxia and facial dysmorphism
Frederike Leonie Harms, Katta Mohan Girisha, Andrew A. Hardigan, Fanny Kortüm, Anju Shukla, Malik Alawi, Ashwin Dalal, Lauren Brady, Mark Tarnopolsky, Lynne M. Bird, Sophia Ceulemans, Martina Bebin, Kevin M. Bowling, Susan M. Hiatt, Edward J. Lose, Michelle Primiano, Wendy K. Chung, Jane Juusola, Zeynep C. Akdemir, Matthew Bainbridge, Wu-Lin Charng, Margaret Drummond-Borg, Mohammad K. Eldomery, Ayman W. El-Hattab, Mohammed A.M. Saleh, Stéphane Beziéau, Benjamin Cogné, Bertrand Isidor, Sébastien Küry, James R. Lupski, Richard M. Myers, Gregory M. Cooper, Kerstin Kutsche
bioRxiv 067454; doi: https://doi.org/10.1101/067454
Mutations in EBF3 disturb transcriptional profiles and underlie a novel syndrome of intellectual disability, ataxia and facial dysmorphism
Frederike Leonie Harms, Katta Mohan Girisha, Andrew A. Hardigan, Fanny Kortüm, Anju Shukla, Malik Alawi, Ashwin Dalal, Lauren Brady, Mark Tarnopolsky, Lynne M. Bird, Sophia Ceulemans, Martina Bebin, Kevin M. Bowling, Susan M. Hiatt, Edward J. Lose, Michelle Primiano, Wendy K. Chung, Jane Juusola, Zeynep C. Akdemir, Matthew Bainbridge, Wu-Lin Charng, Margaret Drummond-Borg, Mohammad K. Eldomery, Ayman W. El-Hattab, Mohammed A.M. Saleh, Stéphane Beziéau, Benjamin Cogné, Bertrand Isidor, Sébastien Küry, James R. Lupski, Richard M. Myers, Gregory M. Cooper, Kerstin Kutsche
bioRxiv 067454; doi: https://doi.org/10.1101/067454
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