De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

DDD Study

Research output: Contribution to journalArticle

Abstract

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

Original languageEnglish
JournalAmerican Journal of Human Genetics
DOIs
Publication statusE-pub ahead of print - Jul 2 2019

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Dimerization
Transcriptional Activation
Developmental Disabilities
Energy Transfer
Brain
Luciferases
Intellectual Disability
Genes
Ear
Proteins
Transcription Factors
Language
Central Nervous System
Alleles
Neurodevelopmental Disorders

Cite this

@article{93dfd5fca167489bb8f3c0b3f9fc06d6,
title = "De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder",
abstract = "POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.",
author = "{DDD Study} and {Snijders Blok}, Lot and Tjitske Kleefstra and Hanka Venselaar and Saskia Maas and Kroes, {Hester Y} and Lachmeijer, {Augusta M A} and {van Gassen}, {Koen L I} and Firth, {Helen V} and Susan Tomkins and Simon Bodek and Katrin {\~O}unap and Wojcik, {Monica H} and Christopher Cunniff and Katherine Bergstrom and Zo{\"e} Powis and Sha Tang and Shinde, {Deepali N} and Catherine Au and Iglesias, {Alejandro D} and Kosuke Izumi and Jacqueline Leonard and {Abou Tayoun}, Ahmad and Baker, {Samuel W} and Marco Tartaglia and Marcello Niceta and Dentici, {Maria Lisa} and Nobuhiko Okamoto and Noriko Miyake and Naomichi Matsumoto and Antonio Vitobello and Laurence Faivre and Christophe Philippe and Christian Gilissen and Laurens Wiel and Rolph Pfundt and Pelagia Deriziotis and Brunner, {Han G} and Fisher, {Simon E}",
note = "Copyright {\circledC} 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = "7",
day = "2",
doi = "10.1016/j.ajhg.2019.06.007",
language = "English",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",

}

TY - JOUR

T1 - De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

AU - DDD Study

AU - Snijders Blok, Lot

AU - Kleefstra, Tjitske

AU - Venselaar, Hanka

AU - Maas, Saskia

AU - Kroes, Hester Y

AU - Lachmeijer, Augusta M A

AU - van Gassen, Koen L I

AU - Firth, Helen V

AU - Tomkins, Susan

AU - Bodek, Simon

AU - Õunap, Katrin

AU - Wojcik, Monica H

AU - Cunniff, Christopher

AU - Bergstrom, Katherine

AU - Powis, Zoë

AU - Tang, Sha

AU - Shinde, Deepali N

AU - Au, Catherine

AU - Iglesias, Alejandro D

AU - Izumi, Kosuke

AU - Leonard, Jacqueline

AU - Abou Tayoun, Ahmad

AU - Baker, Samuel W

AU - Tartaglia, Marco

AU - Niceta, Marcello

AU - Dentici, Maria Lisa

AU - Okamoto, Nobuhiko

AU - Miyake, Noriko

AU - Matsumoto, Naomichi

AU - Vitobello, Antonio

AU - Faivre, Laurence

AU - Philippe, Christophe

AU - Gilissen, Christian

AU - Wiel, Laurens

AU - Pfundt, Rolph

AU - Deriziotis, Pelagia

AU - Brunner, Han G

AU - Fisher, Simon E

N1 - Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2019/7/2

Y1 - 2019/7/2

N2 - POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

AB - POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

U2 - 10.1016/j.ajhg.2019.06.007

DO - 10.1016/j.ajhg.2019.06.007

M3 - Article

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

ER -