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<p>Voltage-gated calcium channels (VGCCs) are essential for neuronal excitability and synapse transmission as well as gene transcription regulation controlling cellular differentiation and survival. Recently, genetic variants in the <i>CACNA1D</i> gene, which encodes the α<sub>1</sub>-subunit of voltage-gated Ca<sub>v</sub>1.3 L-type Ca<sup>2+</sup>-channels, were linked to neurodevelopmental disorders, but their pathophysiological role on neuronal activity and development in a human background remains unknown. Here, we report the first functional characterization of a patient-derived iPSC-based disease model of the <i>CACNA1D</i> L271H variant. We observed that Ca<sub>v</sub>1.3 is the dominantly expressed L-type calcium channel isoform in neural progenitor cells (NPCs). NPCs expressing the L271H variant exhibit increased spontaneous calcium transients compared to the WT controls. Differentiated L271H-variant midbrain neurons show a more depolarized resting membrane potential and reduced excitability. Cortical organoids generated from the L271H-iPSCs contain fewer and smaller ventricular-like structures indicating impaired cellular organization. We identify spatial distortion of radial glial cell distribution and accelerated neuronal differentiation in patient-derived organoids as judged by premature intermediate progenitor cell and neuron emergence. Unbiased transcriptomic analysis revealed numerous dysregulated genes that according to gene ontology analysis were associated with “transcriptional regulation”, “CNS development”, and “neurogenesis” including <i>PTN, POU3F2, CNTN4</i> and <i>AUTS2</i>. These findings imply that disease-causing Ca<sub>v</sub>1.3 variants alter ion homeostasis, result in aberrant neuronal function and distort human neurodevelopment, contributing to the complex disease phenotype observed in patients with high-risk <i>CACNA1D</i> variants.</p>

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Aberrant calcium signaling and neuronal activity in the L271H CACNA1D (Cav1.3) iPSC model of neurodevelopmental disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月9日

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  • Marcel Tisch,
  • Stefanie M. Geisler,
  • Elisa Gabassi,
  • Quirin Schlemmer,
  • Miriam Lechner,
  • Julia-Anna Ulz,
  • Marta Suarez-Cubero,
  • Laura De Gaetano,
  • Angeliki Spathopoulou,
  • Jörg Striessnig,
  • Nadine J. Ortner,
  • Katharina Günther,
  • Petronel Tuluc,
  • Frank Edenhofer

摘要

Voltage-gated calcium channels (VGCCs) are essential for neuronal excitability and synapse transmission as well as gene transcription regulation controlling cellular differentiation and survival. Recently, genetic variants in the CACNA1D gene, which encodes the α1-subunit of voltage-gated Cav1.3 L-type Ca2+-channels, were linked to neurodevelopmental disorders, but their pathophysiological role on neuronal activity and development in a human background remains unknown. Here, we report the first functional characterization of a patient-derived iPSC-based disease model of the CACNA1D L271H variant. We observed that Cav1.3 is the dominantly expressed L-type calcium channel isoform in neural progenitor cells (NPCs). NPCs expressing the L271H variant exhibit increased spontaneous calcium transients compared to the WT controls. Differentiated L271H-variant midbrain neurons show a more depolarized resting membrane potential and reduced excitability. Cortical organoids generated from the L271H-iPSCs contain fewer and smaller ventricular-like structures indicating impaired cellular organization. We identify spatial distortion of radial glial cell distribution and accelerated neuronal differentiation in patient-derived organoids as judged by premature intermediate progenitor cell and neuron emergence. Unbiased transcriptomic analysis revealed numerous dysregulated genes that according to gene ontology analysis were associated with “transcriptional regulation”, “CNS development”, and “neurogenesis” including PTN, POU3F2, CNTN4 and AUTS2. These findings imply that disease-causing Cav1.3 variants alter ion homeostasis, result in aberrant neuronal function and distort human neurodevelopment, contributing to the complex disease phenotype observed in patients with high-risk CACNA1D variants.