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<p>Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting 5% of children and 2.5% of adults worldwide. ADHD is considered a polygenic disorder caused by a combination of both common and rare risk variants, each with low individual effect size. The Vps10p domain receptor SorCS2 is involved in neuronal development and synaptic plasticity by modulating brain-derived neurotrophic factor (BDNF) signaling. We here describe the identification and characterization of a heterozygous damaging variant in the <i>SORCS2</i> gene found in two members of a family with persistent ADHD. The <i>SORCS2</i> variant results in an arginine to tryptophan substitution in the 10CC region of the extracellular Vps10p domain, leading to aberrant posttranslational receptor processing, subcellular localization and ligand binding. Furthermore, the variant abrogates BDNF signaling in a dominant negative manner. Biochemical analysis of additional rare missense variants from ADHD cohorts suggested that SorCS2 structural stability and function is susceptible to such variation in the Vps10p domain. Our findings provide insights into how low frequency damaging variants in <i>SORCS2</i> may contribute to the risk of ADHD.</p>

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A low frequency damaging SORCS2 variant identified in a family with ADHD compromises receptor stability and quenches activity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月18日

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  • Mathias Kaas,
  • Sarah Broholt Dinesen,
  • Ole Ahlgreen,
  • Peder Madsen,
  • Simon Mølgaard,
  • Anders Dalby,
  • Camilla Gustafsen,
  • Ditte Olsen,
  • Jinjie Duan,
  • Joachim Vilstrup,
  • Jonas Lende,
  • Sanne Nordestgaard,
  • Tetyana Zayats,
  • Per Morten Knappskog,
  • Stefan Johansson,
  • Gesche Neckelmann,
  • Barbara Franke,
  • Søren Thirup,
  • Anders Børglum,
  • Andreas Reif,
  • Christian Vægter,
  • Ditte Demontis,
  • Jan Haavik,
  • Simon Glerup,
  • Sune Skeldal

摘要

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting 5% of children and 2.5% of adults worldwide. ADHD is considered a polygenic disorder caused by a combination of both common and rare risk variants, each with low individual effect size. The Vps10p domain receptor SorCS2 is involved in neuronal development and synaptic plasticity by modulating brain-derived neurotrophic factor (BDNF) signaling. We here describe the identification and characterization of a heterozygous damaging variant in the SORCS2 gene found in two members of a family with persistent ADHD. The SORCS2 variant results in an arginine to tryptophan substitution in the 10CC region of the extracellular Vps10p domain, leading to aberrant posttranslational receptor processing, subcellular localization and ligand binding. Furthermore, the variant abrogates BDNF signaling in a dominant negative manner. Biochemical analysis of additional rare missense variants from ADHD cohorts suggested that SorCS2 structural stability and function is susceptible to such variation in the Vps10p domain. Our findings provide insights into how low frequency damaging variants in SORCS2 may contribute to the risk of ADHD.