Abstract
CACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.
Highlights
Voltage-gated Ca2+ (CaV) 2.1 channels are the most abundant CaV channel in the mammalian brain where they are expressed in all brain structures with high expression in the cerebellum [1, 2]. CaV channels are formed by the pore-forming CaVα1 subunit and ancillary CaVα2δ and CaVβ subunits
The voltage sensor is localized to the S4 segment of each domain, whereas S5 and S6 and their connecting loop form the ion conduction pathway of the channel (Fig. 1)
Hypotonia was present from the newborn period and he first presented to attention in Clinical genetics at nearly 3 years of age for evaluation of his developmental delay and hypotonia
Summary
Voltage-gated Ca2+ (CaV) 2.1 channels are the most abundant CaV channel in the mammalian brain where they are expressed in all brain structures with high expression in the cerebellum [1, 2]. CaV channels are formed by the pore-forming CaVα1 subunit and ancillary CaVα2δ and CaVβ subunits. Voltage-gated Ca2+ (CaV) 2.1 channels are the most abundant CaV channel in the mammalian brain where they are expressed in all brain structures with high expression in the cerebellum [1, 2]. The voltage sensor is localized to the S4 segment of each domain, whereas S5 and S6 and their connecting loop form the ion conduction pathway of the channel (Fig. 1). CaV2.1 channels couple efficiently to the vesicular release machinery and are involved in fast synaptic transmission [3, 4]. On postsynaptic neurons they play a role in Ca2+.
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