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

Frederike Leonie Harms, Katta M. 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 & 13 others Wu Lin Charng, Margaret Drummond-Borg, Mohammad K. Eldomery, Ayman W. El-Hattab, Mohammed A.M. Saleh, Stéphane Bézieau, Benjamin Cogné, Bertrand Isidor, Sébastien Küry, James R. Lupski, Richard M. Myers, Gregory M. Cooper, Kerstin Kutsche

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)117-127
Number of pages11
JournalAmerican Journal of Human Genetics
Volume100
Issue number1
DOIs
Publication statusPublished - 05-01-2017

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Mutant Proteins
Ataxia
Intellectual Disability
Exome
Language Development Disorders
Mutation
Aptitude
DNA
Amino Acid Substitution
Regulator Genes
Reporter Genes
Transcriptional Activation
Chromatin
Cytoplasm
B-Lymphocytes
Transcription Factors
Genome
RNA
3'-(1-butylphosphoryl)adenosine
Neurodevelopmental Disorders

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Harms, Frederike Leonie ; Girisha, Katta M. ; Hardigan, Andrew A. ; Kortüm, Fanny ; Shukla, Anju ; Alawi, Malik ; Dalal, Ashwin ; Brady, Lauren ; Tarnopolsky, Mark ; Bird, Lynne M. ; Ceulemans, Sophia ; Bebin, Martina ; Bowling, Kevin M. ; Hiatt, Susan M. ; Lose, Edward J. ; Primiano, Michelle ; Chung, Wendy K. ; Juusola, Jane ; Akdemir, Zeynep C. ; Bainbridge, Matthew ; Charng, Wu Lin ; Drummond-Borg, Margaret ; Eldomery, Mohammad K. ; El-Hattab, Ayman W. ; Saleh, Mohammed A.M. ; Bézieau, Stéphane ; Cogné, Benjamin ; Isidor, Bertrand ; Küry, Sébastien ; Lupski, James R. ; Myers, Richard M. ; Cooper, Gregory M. ; Kutsche, Kerstin. / Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism. In: American Journal of Human Genetics. 2017 ; Vol. 100, No. 1. pp. 117-127.
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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.",
author = "Harms, {Frederike Leonie} and Girisha, {Katta M.} and Hardigan, {Andrew A.} and Fanny Kort{\"u}m and Anju Shukla and Malik Alawi and Ashwin Dalal and Lauren Brady and Mark Tarnopolsky and Bird, {Lynne M.} and Sophia Ceulemans and Martina Bebin and Bowling, {Kevin M.} and Hiatt, {Susan M.} and Lose, {Edward J.} and Michelle Primiano and Chung, {Wendy K.} and Jane Juusola and Akdemir, {Zeynep C.} and Matthew Bainbridge and Charng, {Wu Lin} and Margaret Drummond-Borg and Eldomery, {Mohammad K.} and El-Hattab, {Ayman W.} and Saleh, {Mohammed A.M.} and St{\'e}phane B{\'e}zieau and Benjamin Cogn{\'e} and Bertrand Isidor and S{\'e}bastien K{\"u}ry and Lupski, {James R.} and Myers, {Richard M.} and Cooper, {Gregory M.} and Kerstin Kutsche",
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Harms, FL, 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, WL, 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 2017, 'Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism', American Journal of Human Genetics, vol. 100, no. 1, pp. 117-127. https://doi.org/10.1016/j.ajhg.2016.11.012

Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism. / Harms, Frederike Leonie; Girisha, Katta M.; Hardigan, Andrew A.; Kortüm, Fanny; Shukla, Anju; Alawi, Malik; Dalal, Ashwin; Brady, Lauren; Tarnopolsky, Mark; Bird, Lynne M.; Ceulemans, Sophia; Bebin, Martina; Bowling, Kevin M.; Hiatt, Susan M.; Lose, Edward J.; Primiano, Michelle; Chung, Wendy K.; Juusola, Jane; Akdemir, Zeynep C.; Bainbridge, Matthew; Charng, Wu Lin; Drummond-Borg, Margaret; Eldomery, Mohammad K.; El-Hattab, Ayman W.; Saleh, Mohammed A.M.; Bézieau, Stéphane; Cogné, Benjamin; Isidor, Bertrand; Küry, Sébastien; Lupski, James R.; Myers, Richard M.; Cooper, Gregory M.; Kutsche, Kerstin.

In: American Journal of Human Genetics, Vol. 100, No. 1, 05.01.2017, p. 117-127.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism

AU - Harms, Frederike Leonie

AU - Girisha, Katta M.

AU - Hardigan, Andrew A.

AU - Kortüm, Fanny

AU - Shukla, Anju

AU - Alawi, Malik

AU - Dalal, Ashwin

AU - Brady, Lauren

AU - Tarnopolsky, Mark

AU - Bird, Lynne M.

AU - Ceulemans, Sophia

AU - Bebin, Martina

AU - Bowling, Kevin M.

AU - Hiatt, Susan M.

AU - Lose, Edward J.

AU - Primiano, Michelle

AU - Chung, Wendy K.

AU - Juusola, Jane

AU - Akdemir, Zeynep C.

AU - Bainbridge, Matthew

AU - Charng, Wu Lin

AU - Drummond-Borg, Margaret

AU - Eldomery, Mohammad K.

AU - El-Hattab, Ayman W.

AU - Saleh, Mohammed A.M.

AU - Bézieau, Stéphane

AU - Cogné, Benjamin

AU - Isidor, Bertrand

AU - Küry, Sébastien

AU - Lupski, James R.

AU - Myers, Richard M.

AU - Cooper, Gregory M.

AU - Kutsche, Kerstin

PY - 2017/1/5

Y1 - 2017/1/5

N2 - 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.

AB - 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.

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