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New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy

Pinggera, Alexandra, Mackenroth, Luisa, Rump, Andreas, Schallner, Jens, Beleggia, Filippo, Wollnik, Bernd, Striessnig, Jörg·2017·Human Molecular Genetics
DOI 10.1093/hmg/ddx175PMC PMC5886262
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Figure 1 (A) The patient carrying a de novo missense mutation in Cav1.3 displayed ASD accompanied by developmental delay, epilepsy and muscular hypotonia. (B) Transmembrane topology of the pore forming α1-subunit. The α1-subunit consists of four homologous repeats, each comprising six transmembrane segments connected by extra- and intracellular linkers. Segments one to four of each domain form the voltage sensing domain and segments five to six build the pore (for review see Ref. 48). Mutation V401L (solid arrow), is localized in the activation gate in segment six of domain I in exon 8a, one of two alternatively spliced exons. Furthermore, Cav1.3 undergoes alternative splicing in the C-terminus. Usage of one of two alternative exons, either 42A or 43s results in stop codons (bars) giving rise to two C-terminal short splice variants, partially or completely lacking the C-terminal modulator (CTM) formed by PCRD and DCRD domains (16–18). EF, pre-IQ and IQ are interaction sites for calmodulin (CaM).
Figure 1 (A) The patient carrying a de novo missense mutation in Cav1.3 displayed ASD accompanied by developmental delay, epilepsy and muscular hypotonia. (B) Transmembrane topology of the pore forming α1-subunit. The α1-subunit consists of four homologous repeats, each comprising six transmembrane segments connected by extra- and intracellular linkers. Segments one to four of each domain form the voltage sensing domain and segments five to six build the pore (for review see Ref. 48). Mutation V401L (solid arrow), is localized in the activation gate in segment six of domain I in exon 8a, one of two alternatively spliced exons. Furthermore, Cav1.3 undergoes alternative splicing in the C-terminus. Usage of one of two alternative exons, either 42A or 43s results in stop codons (bars) giving rise to two C-terminal short splice variants, partially or completely lacking the C-terminal modulator (CTM) formed by PCRD and DCRD domains (16–18). EF, pre-IQ and IQ are interaction sites for calmodulin (CaM).CC BY · PubMed Central
Figure 2 Mutation V401L affects channel gating. (A + C) current-voltage relationships (ICa, mean ± S.E.M.) of wild-type (WT) vs. mutant C-terminal long (A) and short (C) Cav1.3 splice variants from parallel transfections. Mutation V401L significantly enhanced current densities in both splice variants, also shown by the boxplots and representative traces, obtained from depolarization to the maximal voltage, in the insets (median (5/95 percentile) [pA/pF]: WTL: −20.0 (−47.0/−6.21), n = 71; V401LL: −28.5 (−70.2/−8.18), n = 59; P < 0.001 against WTL; WTS: −10.3 (−16.8/−4.86), n = 17; V401LS: −17.6 (−35.9/−6.16), n = 15, P = 0.0345 against WTS, Mann Whitney test for both). (B + D) Voltage dependence of ICa activation and inactivation of WT and mutant long (B) and short (D) Cav1.3 splice variants. Mutation V401L significantly shifted voltage dependence of activation and inactivation to more negative potentials in both splice variants. Data shown as mean ± S.E.M., for parameters and statistics see Table 1. (E) Ratio of Itail vs. area of ON-gating charge movement (QON). Mutation V401LL resulted in a higher Itail/QON ratio, indicating a higher estimated open probability. The following slopes were obtained by linear regression: WTL: −9.29 ± 0.82 (R2=0.71); V401LL: −28.1 ± 1.93 (R2=0.8072). Slopes were significantly different (P < 0.0001; (F) (DFn/DFd)=71.4 (1/104); linear regression, F-test, Graphpad PRISM 5.0). Representative traces upon depolarization to the reversal potential are shown to the right. Data were collected from more than three independent transfections. Experiments with poor voltage-clamp were always excluded from analysis.
Figure 2 Mutation V401L affects channel gating. (A + C) current-voltage relationships (ICa, mean ± S.E.M.) of wild-type (WT) vs. mutant C-terminal long (A) and short (C) Cav1.3 splice variants from parallel transfections. Mutation V401L significantly enhanced current densities in both splice variants, also shown by the boxplots and representative traces, obtained from depolarization to the maximal voltage, in the insets (median (5/95 percentile) [pA/pF]: WTL: −20.0 (−47.0/−6.21), n = 71; V401LL: −28.5 (−70.2/−8.18), n = 59; P < 0.001 against WTL; WTS: −10.3 (−16.8/−4.86), n = 17; V401LS: −17.6 (−35.9/−6.16), n = 15, P = 0.0345 against WTS, Mann Whitney test for both). (B + D) Voltage dependence of ICa activation and inactivation of WT and mutant long (B) and short (D) Cav1.3 splice variants. Mutation V401L significantly shifted voltage dependence of activation and inactivation to more negative potentials in both splice variants. Data shown as mean ± S.E.M., for parameters and statistics see Table 1. (E) Ratio of Itail vs. area of ON-gating charge movement (QON). Mutation V401LL resulted in a higher Itail/QON ratio, indicating a higher estimated open probability. The following slopes were obtained by linear regression: WTL: −9.29 ± 0.82 (R2=0.71); V401LL: −28.1 ± 1.93 (R2=0.8072). Slopes were significantly different (P < 0.0001; (F) (DFn/DFd)=71.4 (1/104); linear regression, F-test, Graphpad PRISM 5.0). Representative traces upon depolarization to the reversal potential are shown to the right. Data were collected from more than three independent transfections. Experiments with poor voltage-clamp were always excluded from analysis.CC BY · PubMed Central
Figure 3 Mutation V401L alters channel inactivation. (A + B) 5-s inactivation upon depolarization to Vmax with Ca2+ (left) and Ba2+ (right) as charge carrier. Mutation V401L significantly reduced ICa inactvation as evident from the inset showing only the first 500 ms, but not IBa inactivation when introduced into the long splice variant (A). When present in the short splice, V401L slowed both ICa and IBa inactivation (B). Traces shown as mean ± S.E.M., for parameters and statistics see Table 1 and 2. (C + D) Recovery from ICa inactivation (mean ± S.E.M.). Mutation V401L resulted in significantly faster recovery from inactivation in both, long (τ as mean ± S.E.M. [ms]: WTL: 121.5 ± 18.3, n = 9; V401LL: 83.8 ± 6.02, n = 11; P = 0.048, unpaired student’s t-test) (C) and short (τ as mean ± S.E.M. [ms]: WTS: 267.2 ± 14.0, n = 9; V401LS: 167.8 ± 14.3, n = 10; P < 0.0001, unpaired student’s t-test) (D) splice variants. Insets show the first 500 ms. Data were fitted using a mono-exponential equation. (E + F) Voltage dependence of Ca2+ dependent inactivation (CDI) of WT and mutant long (E) and short (F) splice variants. r250 represents the fraction of the peak current remaining after 250 ms upon depolarization with Ca2+ (closed symbols) of Ba2+ (open symbols) as charge carrier of WT (left panel) vs. V401L (middle panel), n-numbers are given in parentheses. Parameter f represents the difference of r250 among ICa and IBa demonstrating the strenght of CDI (right panel). In both splice variants, mutation V401L resulted in an altered CDI over a broad voltage range, as evident by the f-parameters in E and F (right panel, two way ANOVA of f-parameters followed by Bonferroni post-hoc test, *P < 0.05, **P < 0.01, ***P < 0.001, separate analysis for long and short splice variants). Data were collected from more than three independent transfections.
Figure 3 Mutation V401L alters channel inactivation. (A + B) 5-s inactivation upon depolarization to Vmax with Ca2+ (left) and Ba2+ (right) as charge carrier. Mutation V401L significantly reduced ICa inactvation as evident from the inset showing only the first 500 ms, but not IBa inactivation when introduced into the long splice variant (A). When present in the short splice, V401L slowed both ICa and IBa inactivation (B). Traces shown as mean ± S.E.M., for parameters and statistics see Table 1 and 2. (C + D) Recovery from ICa inactivation (mean ± S.E.M.). Mutation V401L resulted in significantly faster recovery from inactivation in both, long (τ as mean ± S.E.M. [ms]: WTL: 121.5 ± 18.3, n = 9; V401LL: 83.8 ± 6.02, n = 11; P = 0.048, unpaired student’s t-test) (C) and short (τ as mean ± S.E.M. [ms]: WTS: 267.2 ± 14.0, n = 9; V401LS: 167.8 ± 14.3, n = 10; P < 0.0001, unpaired student’s t-test) (D) splice variants. Insets show the first 500 ms. Data were fitted using a mono-exponential equation. (E + F) Voltage dependence of Ca2+ dependent inactivation (CDI) of WT and mutant long (E) and short (F) splice variants. r250 represents the fraction of the peak current remaining after 250 ms upon depolarization with Ca2+ (closed symbols) of Ba2+ (open symbols) as charge carrier of WT (left panel) vs. V401L (middle panel), n-numbers are given in parentheses. Parameter f represents the difference of r250 among ICa and IBa demonstrating the strenght of CDI (right panel). In both splice variants, mutation V401L resulted in an altered CDI over a broad voltage range, as evident by the f-parameters in E and F (right panel, two way ANOVA of f-parameters followed by Bonferroni post-hoc test, *P < 0.05, **P < 0.01, ***P < 0.001, separate analysis for long and short splice variants). Data were collected from more than three independent transfections.CC BY · PubMed Central
Figure 4 Mutation V401L increases the window current. (A + B) Determination of the basal window current for long (A) and short (B) splice variants. Curves were obtained by multiplying the product of the steady-state activation and inactivation in Fig. 2B + D, with the corresponding current densities at the given potentials in Fig. 2A + C, respectively. See Methods for details. Mutation V401L significantly increased the window current in both splice variants (A, P < 0.05; B, P < 0.01; two-way ANOVA). C + D: Determination of the persistent current for long (C) and short (D) splice variants. Remaining current after 5-s depolarizations to different potentials expressed as fraction of maximal possible inward current, assessed by a prepulse to Vmax in the same sweep. Data shown as mean ± S.E.M., n-numbers are given in parentheses. When introduced into the long splice variant V401L resulted in an enhanced persistent current at − 10 to +10 mV (*P < 0.05, **P < 0.01, two-way ANOVA, followed by Bonferroni post-hoc test).
Figure 4 Mutation V401L increases the window current. (A + B) Determination of the basal window current for long (A) and short (B) splice variants. Curves were obtained by multiplying the product of the steady-state activation and inactivation in Fig. 2B + D, with the corresponding current densities at the given potentials in Fig. 2A + C, respectively. See Methods for details. Mutation V401L significantly increased the window current in both splice variants (A, P < 0.05; B, P < 0.01; two-way ANOVA). C + D: Determination of the persistent current for long (C) and short (D) splice variants. Remaining current after 5-s depolarizations to different potentials expressed as fraction of maximal possible inward current, assessed by a prepulse to Vmax in the same sweep. Data shown as mean ± S.E.M., n-numbers are given in parentheses. When introduced into the long splice variant V401L resulted in an enhanced persistent current at − 10 to +10 mV (*P < 0.05, **P < 0.01, two-way ANOVA, followed by Bonferroni post-hoc test).CC BY · PubMed Central
Figure 5 Mutation V401L alters isradipine sensitivity at HP − 80 mV (circles and dashed lines; IC50 [%]: WTL: 154.7 ± 1.07; V401LL: 97.5 ± 1.15; P = 0.0278, sum-of-squares F-test) but not at HP − 50 mV (squares and continuous lines; IC50 [%]: WTL: 51.0 ± 1.17; V401LL: 44.5 ± 1.07). Data shown as mean ± S.E.M., fits were performed with Hill slope 1, top was fixed to 1. N-numbers are 8–14 for the individual data points.
Figure 5 Mutation V401L alters isradipine sensitivity at HP − 80 mV (circles and dashed lines; IC50 [%]: WTL: 154.7 ± 1.07; V401LL: 97.5 ± 1.15; P = 0.0278, sum-of-squares F-test) but not at HP − 50 mV (squares and continuous lines; IC50 [%]: WTL: 51.0 ± 1.17; V401LL: 44.5 ± 1.07). Data shown as mean ± S.E.M., fits were performed with Hill slope 1, top was fixed to 1. N-numbers are 8–14 for the individual data points.CC BY · PubMed Central

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Metadata

Authors
Pinggera, A., Mackenroth, L., Rump, A., Schallner, J., Beleggia, F., Wollnik, B., & Striessnig, J.
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2017-05-04
Volume
26
Issue
15
Pages
2923-2932
ISSN
  • 0964-6906
  • 1460-2083
DOI
10.1093/hmg/ddx175
PMC
PMC5886262
Cited by
112
References
8
Language
en
Funders
Austrian Science Fund (F44020, P27809, W11)

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Pinggera, A., Mackenroth, L., Rump, A., Schallner, J., Beleggia, F., Wollnik, B., & Striessnig, J. (2017). New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddx175

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