TY - JOUR
T1 - De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder
AU - Blok, Lot Snijders
AU - Kleefstra, Tjitske
AU - Venselaar, Hanka
AU - Maas, Saskia
AU - Kroes, Hester Y.
AU - Lachmeijer, Augusta M. A.
AU - van Gassen, Koen L.
AU - Firth, Helen
AU - Tomkins, Susan
AU - Bodek, Simon
AU - Study, The D. D. D.
AU - Ounap, Katrin
AU - Wojcik, Monica H.
AU - Cunniff, Christopher
AU - Bergstrom, Katherine
AU - Powis, Zoe
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.
PY - 2019/8
Y1 - 2019/8
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.
KW - TRANSCRIPTIONAL REGULATION
KW - PROTEINS
KW - BINDING
KW - BRN-2
KW - HOMODIMERIZATION
KW - EXPRESSION
KW - SPEECH
KW - GENES
U2 - 10.1016/j.ajhg.2019.06.007
DO - 10.1016/j.ajhg.2019.06.007
M3 - Article
C2 - 31303265
SN - 0002-9297
VL - 105
SP - 403
EP - 412
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -