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

OZAWA Junichi OHNO Seiko 20610025 0000-0003-1209-8896 MELGARI Dario WANG Qi FUKUYAMA Megumi 60625771 TOYODA Futoshi 90324574 MAKIYAMA Takeru YOSHINAGA Masao SUZUKI Hiroshi 60791382 0000-0001-7003-0123 SAITOH Akihiko 30531389 HORIE Minoru 90183938 0000-0002-9029-2339 滋賀医科大学

2022.11.08

概要

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 Ca2+ channels (Cav1.2), 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 CaV1.2 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 Ca2+ currents by significantly delaying CaV1.2 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.

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参考文献

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