Mean Total scores of ADHD- symptoms (DCL-HKS, DISYPS) for the four diagnostic groups

<p><b>Copyright information:</b></p><p>Taken from "Inhibition, flexibility, working memory and planning in autism spectrum disorders with and without comorbid ADHD-symptoms"</p><p>http://www.capmh.com/content/2/1/4</p><p>Child and Adolescent Psychiatry and Mental Health 2008;2():4-4.</p><p>Published online 31 Jan 2008</p><p>PMCID:PMC2276205.</p><p></p

Mean Total scores of ASD-symptoms (DCL-TES, DISYPS) for the four diagnostic groups

<p><b>Copyright information:</b></p><p>Taken from "Inhibition, flexibility, working memory and planning in autism spectrum disorders with and without comorbid ADHD-symptoms"</p><p>http://www.capmh.com/content/2/1/4</p><p>Child and Adolescent Psychiatry and Mental Health 2008;2():4-4.</p><p>Published online 31 Jan 2008</p><p>PMCID:PMC2276205.</p><p></p

I–V relationships.

<p>Currents were elicited from −40 to +60 mV in 10 mV increments with 5 mM or 20 mM Ba²⁺, respectively. The holding potential was −100 mV. Current density of the variants p.G167S (N = 11) and p.S197F (N = 8) in (<b>a</b>) and p.F240L (N = 5) in (<b>b</b>) were compared with their respective WTs (β2d_WT: N = 9 and β2dE7c_WT: N = 5).</p

Rare Mutations of <i>CACNB2</i> Found in Autism Spectrum Disease-Affected Families Alter Calcium Channel Function

<div><p>Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits Ca_V1.2 (<i>CACNA1C)</i> and Ca_Vβ2 (<i>CACNB2</i>) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of <i>CACNB2</i> (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba²⁺ currents through calcium channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the <i>CACNA1C</i> mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare <i>CACNB2</i> missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.</p></div

Voltage-dependent steady-state inactivation (a, b) of Ba²⁺ currents through L-type calcium channels.

<p>The ASD mutants p.G167S (N = 4) and p.S197F (N = 6) showed a significantly flattened slope of voltage-dependent inactivation compared to β2d_WT (N = 7). The third mutation β2dE7c_F240L. (N = 5) did not obviously differ from its corresponding β2dE7c_WT (N = 2). Half-inactivation potentials (V0.5_inact) (<b>c</b>) and the slope factors dV (<b>d</b>) were obtained from the fits of individual experiments using the Boltzmann equation and averaging the results. Asterisk (*) marks a statistical significance (P<0.05) compared to the respective WT.</p

Splice scheme of human <i>CACNB2</i> resulting in 9 splice variants of the Ca_Vβ2-subunit with the localization of the three mutations.

<p>Spliced exons are shown in light grey and conserved exons in dark grey. All nine splice variants express the mutation-carrying exon 5, while three of variants contain the localization of the third mutation in exon 7c <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095579#pone.0095579-Buraei1" target="_blank">[10]</a>.</p

Clinical Features of ASD patients with rare mutations in <i>CACNB2</i>.

<p><b>ADI-R</b>, Autism Diagnostic Interview-Revised; <b>ADOS</b>, Diagnostic Observation Schedule-Generic; <b>MRI,</b> magnetic resonance imaging.</p

Time-dependent inactivation.

<p>Representative whole-cell Ba²⁺ current traces (a) of Ca_V1.2/α2δ1 co-expressed with β2d_WT -subunit or co-expressed with the ASD mutants β2d_G167S, β2d_S197F or the β2dE7c_WT or its variant β2dE7c_F240L. The currents were elicited from a holding potential of −100 mV by 150 ms (or 500ms) step depolarization of −40 to +50 mV with 20 mM Ba²⁺ (for β2d variants) or 5 mM Ba²⁺ (for β2dE7c variants), respectively. Analysis of the extent of time-dependent inactivation. (<b>b</b>, <b>c</b>) % Inactivation was analyzed as the remaining fraction of whole-cell current that has not inactivated after 150 ms of depolarization. β2d_WT (N = 12), β2d_G167S (N = 8), β2d_S197F (N = 11) (<b>c</b>) Similar analysis for β2dE7c variants β2dE7c_WT (N = 5), β2dE7c_F240L (N = 6). Asterisk (*) marks a statistical significance (P<0.05) compared to the respective WT, (**) marks P<0.01.</p

Current and voltage parameters (mean ± SEM) of the constructs tested.

<p><b>V0.5_act,</b> Voltage of half-maximal activation; <b>V0.5_inact,</b> half-maximal inactivation voltage, dV, slope factor; −<b>β2d,</b> mock transfected cells;</p><p>*indicates P<0.05 versus corresponding WT.</p

Association of <i>DCKL1</i> genetic variants with psychiatric and cognitive traits.

<p>Markers are ordered from 5′ to 3′ of the gene, anti-sense to the reference sequence. <b>A.</b> Representation of the genomic region covered and of 6 <i>DCLK1</i> transcripts (from top to bottom: <i>DCL</i>, <i>CARP</i>, 2 short variants and 2 long variants). In addition to alternative start sites, the transcripts can be alternatively spliced for part of exon 9, for exon 19 and in the 3′UTR. <b>B.</b> All markers showing nominal association to psychiatric traits in this study or to cognitive traits in our previous study <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035424#pone.0035424-LeHellard1" target="_blank">[16]</a> are displayed. Color code: yellow, P-value between 0.05 and 0.001; orange, P-value between 0.001 and 0.0001; red, P-value<0.0001; white, P-value>0.05; grey, marker not tested in this sample. The markers used in the cross-phenotype analyses are highlighted in red. <b>C.</b> LD between the markers used in the cross-phenotype analyses, and the markers associated with cognitive traits in our previous study <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035424#pone.0035424-LeHellard1" target="_blank">[16]</a>. LD is displayed using a r² scale ranging from r² = 1 in black to r² = 0 in white.</p