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

Lot Snijders Blok*, Tjitske Kleefstra, Hanka Venselaar, Saskia Maas, Hester Y. Kroes, Augusta M. A. Lachmeijer, Koen L. van Gassen, Helen Firth, Susan Tomkins, Simon Bodek, The D. D. D. Study, Katrin Ounap, Monica H. Wojcik, Christopher Cunniff, Katherine Bergstrom, Zoe Powis, Sha Tang, Deepali N. Shinde, Catherine Au, Alejandro D. IglesiasKosuke Izumi, Jacqueline Leonard, Ahmad Abou Tayoun, Samuel W. Baker, Marco Tartaglia, Marcello Niceta, Maria Lisa Dentici, Nobuhiko Okamoto, Noriko Miyake, Naomichi Matsumoto, Antonio Vitobello, Laurence Faivre, Christophe Philippe, Christian Gilissen, Laurens Wiel, Rolph Pfundt, Pelagia Deriziotis, Han G. Brunner, Simon E. Fisher*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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
Pages (from-to)403-412
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - Aug 2019


  • BRN-2

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