Rare Missense Mutations in the Calcium Channel β2 Subunit of Autistic Patients

Calcium channels are crucially involved in brain development and neuronal function. Mutations in the pore-forming Cav subunits of high- and low-voltage dependent calcium channels (VDCC) have been found in patients with autistic syndromes (Splawski et al., Cell 2004;119:19-31; Splawski et al., PNAS 2005;102:8089-96; Splawski et al., JBC 2006;281:22085-91). In Timothy syndrome, the G406R mutation of Cav1.2 results in a reduction of inactivation rate. Such biophysical effects can likewise be induced by the influence of auxiliary VDCC β subunits. For instance, we demonstrated a novel mechanism of β subunit modulation: the inactivation of VDCC is under length-dependent control of the β2 subunit N terminus (Herzig et al., FASEB J 2007;21:1527-38). A similar mechanism operates with the β1 subunit (Jangsangthong et al., Pflugers Arch 2009, in press).Therefore, the β2-subunit gene was screened for mutations in 155 patients with Autistic Spectrum Disorder (ASD). We detected several new variations and compared the genotypes with 375 matching controls. (Male to female ratio for both groups is 1:4.). Statistical analysis of preselected variations showed two significant SNPs in functional intronic regions (χ2 p = 5x10−6 and χ2 p =9x10−3).Furthermore, we also identified several rare ASD-specific missense mutations at the gene locus of the β2 subunit. These mutations occur in highly conserved domains and may lead to alterations in the β2 subunit function, e.g. by interfering with subunit phosphorylation. The affected amino acids are highly conserved among species, suggesting an importance for topology and function of the subunit. We will clone these variations into expression vectors and characterize their functional effects by electrophysiological studies. These studies may provide new insights into molecular mechanisms leading to ASD.