De novo TBR1 mutations in sporadic autism disrupt protein functions

Pelagia Deriziotis, Brian O'Roak, Sarah A. Graham, Sara B. Estruch, Danai Dimitropoulou, Raphael A. Bernier, Jennifer Gerdts, Jay Shendure, Evan E. Eichler, Simon E. Fisher

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

Original languageEnglish (US)
Article number4954
JournalNature Communications
Volume5
DOIs
StatePublished - 2014

Fingerprint

Autistic Disorder
mutations
Missense Mutation
proteins
Mutation
Assays
Language Disorders
Speech Disorders
Proteins
disorders
Transcription Factors
Language
Genes
sequencing
regulators
genes
interactions

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Deriziotis, P., O'Roak, B., Graham, S. A., Estruch, S. B., Dimitropoulou, D., Bernier, R. A., ... Fisher, S. E. (2014). De novo TBR1 mutations in sporadic autism disrupt protein functions. Nature Communications, 5, [4954]. https://doi.org/10.1038/ncomms5954

De novo TBR1 mutations in sporadic autism disrupt protein functions. / Deriziotis, Pelagia; O'Roak, Brian; Graham, Sarah A.; Estruch, Sara B.; Dimitropoulou, Danai; Bernier, Raphael A.; Gerdts, Jennifer; Shendure, Jay; Eichler, Evan E.; Fisher, Simon E.

In: Nature Communications, Vol. 5, 4954, 2014.

Research output: Contribution to journalArticle

Deriziotis, P, O'Roak, B, Graham, SA, Estruch, SB, Dimitropoulou, D, Bernier, RA, Gerdts, J, Shendure, J, Eichler, EE & Fisher, SE 2014, 'De novo TBR1 mutations in sporadic autism disrupt protein functions', Nature Communications, vol. 5, 4954. https://doi.org/10.1038/ncomms5954
Deriziotis P, O'Roak B, Graham SA, Estruch SB, Dimitropoulou D, Bernier RA et al. De novo TBR1 mutations in sporadic autism disrupt protein functions. Nature Communications. 2014;5. 4954. https://doi.org/10.1038/ncomms5954
Deriziotis, Pelagia ; O'Roak, Brian ; Graham, Sarah A. ; Estruch, Sara B. ; Dimitropoulou, Danai ; Bernier, Raphael A. ; Gerdts, Jennifer ; Shendure, Jay ; Eichler, Evan E. ; Fisher, Simon E. / De novo TBR1 mutations in sporadic autism disrupt protein functions. In: Nature Communications. 2014 ; Vol. 5.
@article{b4b77c0edd4540968eef4fd2aca3f9b9,
title = "De novo TBR1 mutations in sporadic autism disrupt protein functions",
abstract = "Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1{\%} of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.",
author = "Pelagia Deriziotis and Brian O'Roak and Graham, {Sarah A.} and Estruch, {Sara B.} and Danai Dimitropoulou and Bernier, {Raphael A.} and Jennifer Gerdts and Jay Shendure and Eichler, {Evan E.} and Fisher, {Simon E.}",
year = "2014",
doi = "10.1038/ncomms5954",
language = "English (US)",
volume = "5",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - De novo TBR1 mutations in sporadic autism disrupt protein functions

AU - Deriziotis, Pelagia

AU - O'Roak, Brian

AU - Graham, Sarah A.

AU - Estruch, Sara B.

AU - Dimitropoulou, Danai

AU - Bernier, Raphael A.

AU - Gerdts, Jennifer

AU - Shendure, Jay

AU - Eichler, Evan E.

AU - Fisher, Simon E.

PY - 2014

Y1 - 2014

N2 - Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

AB - Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

UR - http://www.scopus.com/inward/record.url?scp=84923327027&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923327027&partnerID=8YFLogxK

U2 - 10.1038/ncomms5954

DO - 10.1038/ncomms5954

M3 - Article

C2 - 25232744

AN - SCOPUS:84923327027

VL - 5

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 4954

ER -