The human channel gating–modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice

• DOI: 10.1172/jci.insight.162100
• Publication Date: 2023-09-12T16:00:21Z
• Authors: Nadine J. Ortner; Anupam Sah; Enrica Paradiso; Josef Shin; Strahinja Stojanovic; Niklas Hammer; Maria Haritonova; Nadja T. Hofer; Andrea Marcantoni; Laura Guarina; Petronel Tuluc; Tamara Theiner; Florian Pitterl; Karl Ebner; Herbert Oberacher; Emilio Carbone; Nadia Stefanova; Francesco Ferraguti; Nicolas Singewald; Jochen Roeper; Jörg Striessnig
• Keywords: Neurodevelopmental disorder

Germline de novo missense variants of the CACNA1D gene, encoding pore-forming α1 subunit Cav1.3 L-type Ca2+ channels (LTCCs), have been found in patients with neurodevelopmental and endocrine dysfunction, but their disease-causing potential is unproven. These alter channel gating, enabling enhanced activity, suggesting inhibition as a therapeutic option. Here we provide proof nature such gating-modifying using mice (Cav1.3AG) containing A749G variant reported patient autism spectrum disorder (ASD) intellectual impairment. In heterozygous mutants, native LTCC currents adrenal chromaffin cells exhibited gating changes predicted from heterologous expression. The mutation induced aberrant excitability dorsomedial striatum–projecting substantia nigra dopamine neurons medium spiny dorsal striatum. phenotype observed mutants reproduced many abnormalities described within human disease spectrum, including developmental delay, social deficit, pronounced hyperactivity without major gross neuroanatomy. Despite an approximately 7-fold higher sensitivity A749G-containing to inhibitor isradipine, oral pretreatment over 2 days did not rescue hyperlocomotion. Cav1.3AG confirm pathogenicity point toward pathogenetic role altered signaling midbrain system.