CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels.
Bottom Line: In both cases, these changes are compatible with a gain-of-function phenotype.Our findings have immediate clinical relevance because blockers of LTCCs are available for therapeutic attempts in affected individuals.Patients should also be explored for other symptoms likely resulting from Cav1.3 hyperactivity, in particular, primary aldosteronism.
Affiliation: Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.Show MeSH
Related in: MedlinePlus
Mentions: Depolarizations to the reversal potential revealed an increased ratio of maximal tail current amplitude to integrated QON (Itail/QON [msec−1]: wild-type, 11.1 ± 1.1, n = 28; A749G, 34.1 ± 2.25, n = 20; p < .0001 vs. wild-type, unpaired Student t test). This finding is compatible with a higher channel open probability or conductance or both, a feature previously observed by us also for other Cav1.3 gain-of-function mutations (22). In contrast to A749G, mutation G407R reduced maximal current amplitudes (Figure 2A) and caused no change in activation voltage dependence (Figure 2A and Table 1). However, in contrast to A749G, G407R dramatically slowed the inactivation time course during 5-sec depolarizations. At the end of the 5-sec pulse to Vmax, only 5.12% ± .98% (n = 15) of maximal wild-type and 3.07% ± .37% (n = 6) of A749G current remained, whereas 82.8% ± .04% (n = 13) of G407R current persisted (p < .001 vs. wild-type, Mann-Whitney test) (Figure 2B, inset). The failure of G407R currents to inactivate prevented the measurement of steady-state inactivation parameters. Despite reduced maximal current amplitudes (Figure 2A), the slow inactivation resulted in larger absolute current amplitudes during prolonged depolarization than in wild-type Cav1.3 channels (Figure 2B). The absence of a fast inactivating component (mediated by calcium-dependent inactivation in Cav1.3) (9,36) suggests that calcium-dependent and voltage-dependent inactivation were strongly weakened by the mutation. The smaller current and QON amplitudes were unlikely because of a lower expression of mutant channel protein as demonstrated by Western blots (Figure S2 in Supplement 1).
Affiliation: Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.