Scholarlink

<p>GABA<sub>B</sub> receptors, the G protein-coupled receptors for the neurotransmitter GABA, are essential for regulating neuronal excitability in the brain. Monoallelic de novo missense variants in <i>GABBR1</i> and <i>GABBR2</i>, which encode the receptor subunits, have been associated with neurodevelopmental disorders. Here, we investigated the functional impact of seven de novo missense variants in <i>GABBR1</i> and <i>GABBR2</i> identified in individuals with autism spectrum disorder, intellectual disability, and/or attention deficit/hyperactivity disorder. In vitro functional characterization of these variants revealed a range of gain- and loss-of-function alterations: (i) increased constitutive activity, leading to a corresponding decrease in GABA efficacy; (ii) a significant reduction in GABA potency at the receptor; and (iii) reduced surface expression, resulting in decreased GABA efficacy. While computational predictions indicated pathogenicity for all variants, our study emphasizes the importance of functional studies in clarifying the nature and scope of pharmacological changes—an essential step toward advancing targeted therapies in precision medicine.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Functional signatures of de novo GABBR1 and GABBR2 variants associated with neurodevelopmental disorders

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月9日

查看全文
  • Michal Stawarski,
  • Noa Bielopolski,
  • Ilana Roitman,
  • Karen Fridman,
  • Shane Wald-Altman,
  • Megan Eitel,
  • Benedict Hui,
  • Anneke Vulto-van Silfhout,
  • Alexander P. A. Stegmann,
  • Adela Chirita-Emandi,
  • Jacqueline Eason,
  • Kirsty Bradshaw,
  • Lewis Darnell,
  • Grażyna Kostrzewa,
  • Rafal Ploski,
  • Romane Meurs,
  • Amandine Batté,
  • Stylianos E. Antonarakis,
  • Martin Gassmann,
  • Bernhard Bettler

摘要

GABAB receptors, the G protein-coupled receptors for the neurotransmitter GABA, are essential for regulating neuronal excitability in the brain. Monoallelic de novo missense variants in GABBR1 and GABBR2, which encode the receptor subunits, have been associated with neurodevelopmental disorders. Here, we investigated the functional impact of seven de novo missense variants in GABBR1 and GABBR2 identified in individuals with autism spectrum disorder, intellectual disability, and/or attention deficit/hyperactivity disorder. In vitro functional characterization of these variants revealed a range of gain- and loss-of-function alterations: (i) increased constitutive activity, leading to a corresponding decrease in GABA efficacy; (ii) a significant reduction in GABA potency at the receptor; and (iii) reduced surface expression, resulting in decreased GABA efficacy. While computational predictions indicated pathogenicity for all variants, our study emphasizes the importance of functional studies in clarifying the nature and scope of pharmacological changes—an essential step toward advancing targeted therapies in precision medicine.