Browsing by Author "Harvey, Robert J."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations
    (Elsevier, 2022-09) Dias, Kerith-Rae; Carlston, Colleen M.; Blok, Laura E. R.; De Hayr , Lachlan; Nawaz, Urwah; Evans, Carey-Anne; Bayrak-Toydemir, Pinar; Htun, Stephanie; Zhu, Ying; Ma, Alan; Lynch, Sally Ann; Moorwood, Catherine; Stals , Karen; Ellard, Sian; Bainbridge, Matthew N.; Friedman, Jennifer; Pappas, John G.; Rabin , Rachel; Nowak, Catherine B.; Douglas, Jessica; Wilson, Theodore E.; Guillen Sacoto, Maria J.; Mullegama, Sureni V.; Palculict , Timothy Blake; Kirk, Edwin P.; Pinner, Jason R.; Edwards, Matthew; Montanari, Francesca; Graziano, Claudio; Pippucci, Tommaso; Dingmann, Bri; Glass , Ian; Mefford , Heather C.; Shimoji , Takeyoshi; Suzuki, Toshimitsu; Yamakawa, Kazuhiro; Streff, Haley; Schaaf, Christian P.; Slavotinek, Anne M.; Voineagu , Irina; Carey, John C.; Buckley, Michael F.; Schenck, Annette; Harvey, Robert J.; Roscioli , Tony; Medical and Molecular Genetics, School of Medicine
    Purpose ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. Methods An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. Results ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the Drosophila ZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. Conclusion We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.
  • Thumbnail Image
    Item
    Presence of ethanol-sensitive and ethanol-insensitive glycine receptors in the ventral tegmental area and prefrontal cortex in mice
    (Wiley, 2021) Araya, Anibal; Gallegos, Scarlet; Viveros, Rodrigo; San Martin, Loreto; Muñoz, Braulio; Harvey, Robert J.; Zeilhofer, Hanns U.; Aguayo, Luis G.; Pharmacology and Toxicology, School of Medicine
    Background and purpose: Glycine receptors composed of α1 and β subunits are primarily found in the spinal cord and brainstem and are potentiated by ethanol (10-100 mM). However, much less is known about the presence, composition and ethanol sensitivity of these receptors in higher CNS regions. Here, we examined two regions of the brain reward system, the ventral tegmental area (VTA) and the prefrontal cortex (PFC), to determine their glycine receptor subunit composition and sensitivity to ethanol. Experimental approach: We used Western blot, immunohistochemistry and electrophysiological techniques in three different models: wild-type C57BL/6, glycine receptor subunit α1 knock-in and glycine receptor subunit α2 knockout mice. Key results: Similar levels of α and β receptor subunits were detected in both brain regions, and electrophysiological recordings demonstrated the presence of glycine-activated currents in both areas. Sensitivity of glycine receptors to glycine was lower in the PFC compared with VTA. Picrotoxin only partly blocked the glycine-activated current in the PFC and VTA, indicating that both regions express heteromeric αβ receptors. Glycine receptors in VTA neurons, but not in PFC neurons, were potentiated by ethanol. Conclusion and implications: Glycine receptors in VTA neurons from WT and α2 KO mice were potentiated by ethanol, but not in neurons from the α1 KI mice, supporting the conclusion that α1 glycine receptors are predominantly expressed in the VTA. By contrast, glycine receptors in PFC neurons were not potentiated in any of the mouse models studied, suggesting the presence of α2/α3/α4, rather than α1 glycine receptor subunits.