Increased CaV1.2 late current by a CACNA1C p.R412M variant causes an atypical Timothy syndrome without syndactyly

• Published in: Scientific reports Vol. 12; no. 1; p. 18984
• Main Authors: Ozawa, Junichi, Ohno, Seiko, Melgari, Dario, Wang, Qi, Fukuyama, Megumi, Toyoda, Futoshi, Makiyama, Takeru, Yoshinaga, Masao, Suzuki, Hiroshi, Saitoh, Akihiko, Ai, Tomohiko, Horie, Minoru
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208; 692/4019; Age; Autism; Binding sites; Calcium channels; Calcium channels (voltage-gated); Cardiology; Channel gating; Congenital diseases; Electrocardiography; Genetic screening; Humanities and Social Sciences; Hypoglycemia; Immune system; Inactivation; Long QT syndrome; Medicine; multidisciplinary; Mutation; Patients; Pediatrics; Physiology; Science; Science (multidisciplinary); Seizures; Syndactyly
• DOI: 10.1038/s41598-022-23512-2
• ISSN: 2045-2322

Timothy syndrome (TS) is a rare pleiotropic disorder associated with long QT syndrome, syndactyly, dysmorphic features, and neurological symptoms. Several variants in exon 8 or 8a of CACNA1C , a gene encoding the α-subunit of voltage-gated Ca 2+ channels (Ca v 1.2), are known to cause classical TS. We identified a p.R412M (exon 9) variant in an atypical TS case. The aim of this study was to examine the functional effects of CACNA1C p.R412M on Ca V 1.2 in comparison with those of p.G406R. The index patient was a 2-month-old female infant who suffered from a cardio-pulmonary arrest in association with prolonged QT intervals. She showed dysmorphic facial features and developmental delay, but not syndactyly. Interestingly, she also presented recurrent seizures from 4 months. Genetic tests identified a novel heterozygous CACNA1C variant, p.R412M. Using heterologous expression system with HEK-293 cells, analyses with whole-cell patch-clamp technique revealed that p.R412M caused late Ca 2+ currents by significantly delaying Ca V 1.2 channel inactivation, consistent with the underlying mechanisms of classical TS. A novel CACNA1C variant, p.R412M, was found to be associated with atypical TS through the same mechanism as p.G406R, the variant responsible for classical TS.