1. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder
- Author
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Christopher Cunniff, Laurence Faivre, Simon E. Fisher, Hester Y. Kroes, Catherine Au, Rolph Pfundt, Jacqueline Leonard, Ahmad N. Abou Tayoun, Kosuke Izumi, Katherine Bergstrom, Deepali N. Shinde, Pelagia Deriziotis, Saskia M. Maas, Marcello Niceta, Antonio Vitobello, Sha Tang, Hanka Venselaar, Christophe Philippe, Christian Gilissen, Tjitske Kleefstra, Marco Tartaglia, Helen V. Firth, Nobuhiko Okamoto, Laurens Wiel, Lot Snijders Blok, Naomichi Matsumoto, Maria Lisa Dentici, Han G. Brunner, Samuel W. Baker, Susan Tomkins, Augusta M. A. Lachmeijer, Simon Bodek, Alejandro D. Iglesias, Monica H. Wojcik, Katrin Õunap, Noriko Miyake, Koen L.I. van Gassen, Zöe Powis, The DDD Study, Human Genetics, ANS - Complex Trait Genetics, MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine
- Subjects
0301 basic medicine ,Male ,Protein Conformation ,Sequence Homology ,Language in Interaction ,Transactivation ,0302 clinical medicine ,Neurodevelopmental disorder ,BINDING ,Transcriptional regulation ,Missense mutation ,Genetics(clinical) ,speech/language disorder ,BRET assay ,Child ,de novo variants ,luciferase reporter ,Genetics (clinical) ,Genetics ,TRANSCRIPTIONAL REGULATION ,POU3F3 ,FOXP2 ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,POU3F2 ,SPEECH ,Brain-1 ,intellectual disability ,Female ,Neuroinformatics ,Transcriptional Activation ,EXPRESSION ,GENES ,Genotype ,PROTEINS ,Biology ,BRN-2 ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Report ,medicine ,Humans ,Amino Acid Sequence ,Allele ,Gene ,Transcription factor ,Genetic Association Studies ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Neurodevelopmental Disorders ,Mutation ,POU Domain Factors ,HOMODIMERIZATION ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,030217 neurology & neurosurgery - 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.
- Published
- 2019