Categorising disease families
Until date, mutations in SCN1A have been found in patients with GEFS+,2,5,8,11,14,18,28,E1-
SMEI and SMEB,4-14,E11-E17 intractable childhood epilepsies with frequent generalized
tonic-clonic seizures (ICEGTC),8,E8 cryptogenic generalized epilepsy (CGE), cryptogenic
focal epilepsy (CFE),E18 myoclonic–astaticepilepsy (MAE), severe infantile multifocal
epilepsy (SIMFE), Lennox–Gastaut syndrome (LGS), Panayiotopoulos syndrome (PS),E9
Rasmussen encephalitisE19 and infantile spasm.5,E11 Previous investigations showed that SMEI
and these epileptic syndromes were part of the SRIEE spectrum.5,6,15
Because information about intellectual disability of three GEFS+ families2,E2 was
described in other reports,3,E20,E21 we investigated such information in the previous reports.
Because information about ataxia of the patients was described in another report,E22 we
investigated the information in the report. As our previous investigation of SMEI/SMEB6 did
not examine the presence/absence of ataxia, we re-investigated the clinical symptoms of the
reported patients. Their clinical data (ataxia) are shown in E-Table 1.
E-Table 1. Summary of clinical information of our previous report. The presence/absence of
ataxia in previously reported SMEI patients.
E-Table 1. Presence/absence of ataxia in previously reported SMEI patients
patient mutation gender ataxia phenotype segment
2 R101Q M + SMEB N-terminal
6 W190R F － SMEI S3
38 L1355P F － SMEB S5
51 F1692S F － SMEI S5
52 Y1694C F + SMEI S5
20 M934I F + SMEI S5-S6linker
21 M934I F + SMEB S5-S6linker
23 V944A F + SMEB S5-S6linker
24 R946C F + SMEI S5-S6linker
25 R946C M + SMEB S5-S6linker
26 R946H F + SMEB S5-S6linker
56 Y1781C M － SMEI S6
Physico-chemical properties of amino acid residues
P, PR and HP are the indices of hydrophobicity of the residue. C is defined as the atomic
weight ratio of non-carbon elements in end groups or rings to carbons in the side chain, and
MV is the value of Å of side chain.21
The values of C, P and MV are taken from Table 1 of Ref. 21. The values of PR, HP and
IE are taken from Table 2 of Ref. 24, Table 2 of Ref. 25 and Table 2 of Ref. 23, respectively.
Inclusion and exclusion criteria
As described in Methods, we have categorized all reported missense mutations according
to the ratio of the severe phenotypes that were included in SRIEE.
Most of the previously reported GEFS+ families were included in the GEFS+ group.
Although learning disability and behaviour disturbance were sometime seen in families with
GEFS+, we did not consider them as intellectual disability in this analysis. However, some
families previously described as GEFS+, where there were significant numbers of patients
with intellectual disturbance whose phenotype was considered to be included in the SRIEE
spectrum, were categorized into the intermediate phenotype group.
Several SCN1A missense mutations have been reported in patients with idiopathic
generalized epilepsy. We included such patients with normal intellect into GEFS+ and those
with intellectual disturbance into SRIEE. In the report by Escayg et al.,E1 information about
intellectual ability was not available; however, we categorized four JME/JAE patients with
SCN1A mutations into GEFS+ except those with V699I and T1174S, because JME/JAE
patients usually show normal intellectual ability. We excluded the two mutations from this
analysis because V699I was found in none of the other affected family members and T1174S
was found in normal controls.
Almost all sporadic patients with SMEI and the above mentioned epileptic syndromes
with SCN1A mutation except GEFS+ were categorized into SRIEE in this study.
It has been reported that some patients with familial hemiplegic migraineE23 and with
autismE24 had SCN1A missence mutations. However we excluded them from this study,
because precise information about epilepsy in those families was not available.
We included Rasmussen encephalitis patient with SCN1A missense mutation into SRIEE,
because several studies showed that focal and asymmetrical cerebral atrophy was often
observed in SMEI patients4,E25 and relationship between Rasmussen encephalitis and anti-
GluR3 antibody has still remained to be controversial. E26,E27
In the investigation of the presence/absence of ataxia, only those cases whose histories of
the presence/absence of ataxia were clearly described were included in this study. In regard to
the cases reported by Fujiwara et al.,8 the absence of the description of ataxia was considered
as the absence of ataxia.
Functional analysis of mutant SCN1A channels
We also reviewed previous functional studies of epilepsy-associated mutant SCN1A
channels. We investigated the mutation positions, phenotype of wild-type sodium channels
(rat/human, scn1a or scn4a), co-expressed proteins and their expression patterns
(homogeneously/heterogeneously expressed with wild-type channel), and types of changes in
Confirmation of the validity of the definition of S1–S4 region
In S1–S4 region, both transmembrane segments, lying within the lipid bilayer, and inter-
transmembrane segment linkers, spanning cytoplasmic or extracellular space, are involved.
Any distinction between mutations in those two distinct regions remains unclear. To confirm
the issue, we analyzed differences in changes of the physico-chemical properties between
mutations in transmembrane segments and inter-transmembrane segment linkers.
Statistical analyses of value changes in the physico-chemical properties for missense
mutations in SCN1A in SRIEE, intermediate phenotypes, and GEFS+ patient groups were
compared by nonparametric multiple comparison tests (Dwass, Steel, Chitchlow–Fligner
tests) to determine which pairs differed significantly. Differences in value changes of the
physico-chemical properties in the patients with and without ataxia also were compared by
nonparametric Mann–Whitney’s U-tests. The relationships between disease onset and value
changes in the physico-chemical properties were analyzed using Spearman’s rank correlation
coefficient. Fisher’s exact test was used for statistical analyses of different distribution pattern
in physico-chemical property changes with missense mutations between GEFS+ and SRIEE
groups. The chi-square test was used for the distribution pattern analysis of the missense
mutations in SCN1A among the three groups. All the statistical tests used were two-sided.
Reported SCN1A missense mutations and their phenotypes
Data on disease onset of 122 SRIEE patients4-9,12-14,E2,E4,E8,E15,E17-E19 and
presence/absence of ataxia of 52 patients4-6,8,9,13, E12,E13,E15,E17,E18,E22 were available (Table 1).
In terms of disease onset, we excluded data described in the form of years.
Relationship between clinical symptoms in SCN1A-related epileptic encephalopathies and
value changes in the physico-chemical properties of amino acid residue substitutions
In the analysis of the association between the change in physico-chemical properties and
clinical symptoms, the disease onset of SRIEE patients showed a tendency to correlate
negatively with IE value changes of missense mutations in the whole regions (n = 122, p =
0.06) (Figure 3A) but not in the pore region of SCN1A (n = 73). With respect to missense
mutations in the pore region of SCN1A, the mean IE absolute value changes of SRIEE
patients with ataxia (n = 28, 2.72 ± 0.43; mean ± SEM) were significantly larger than those of
patients without ataxia (n = 8, 0.90 ± 0.56; mean ± SEM) (Figure 3B; p < 0.05).
Confirmation of the validity of the definition of S1–S4 region
In S1–S4 region, the mean value differences of the hydrophobicity indices (HP, P and
PR) in the GEFS+ group were significantly different from those in SRIEE. Compared to the
SRIEE group, the difference in HP value of the GEFS+ group was significantly smaller, both
in transmembrane segments [GEFS+ (n = 6) −2.63 ± 1.65 vs. SRIEE (n = 25) 1.78 ± 0.70
(mean ± SEM); p < 0.05] and inter-transmembrane segment linkers of S1–S4 region [GEFS+
(n = 4) −5.65 ± 0.99 vs. SRIEE (n = 9) 0.49 ± 1.12 (mean ± SEM); p < 0.05]. With regard to
P, the difference in P value of the GEFS+ group tended to be larger than that of the SRIEE
group, both in transmembrane segments [GEFS+ (n = 6) 2.23 ± 1.22 vs. SRIEE (n = 25)
−0.79 ± 0.59 (mean ± SEM); p < 0.10] and inter-transmembrane segment linkers of S1-S4
region [GEFS+ (n = 4) 3.45 ± 1.56 vs. SRIEE (n = 9) −0.54 ± 0.88 (mean ± SEM); p < 0.10].
These changes showed that decreasing hydrophobicity with amino acid replacements were
associated with a more severe phenotype both in transmembrane segments and inter-
transmembrane segment linkers of S1–S4 region.
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E-Table 2. SCN1A mutations whoes functional abnormalities were studied by patch-
E-Table 2. SCN1A mutations whoes functional abnormalities were studied by patch-clamp method.
type expression region Phenotypes persistent Na current current density activation inactivation recovery from innactivation frequency dependence Ref.
W1204R human SCN1A homo alpha1:beta1:beta2=10:1:1 II-III linker GEFS+ ↑ → hyperpolarize E28
W1204R rat scn1a homo alpha:beta=10:1 II-III linker GEFS+ → hyperpolarize hyperpolarize → E29
D1866Y rat scn1a homo alpha1:beta1=10:1 C-terminal GEFS+ ↑ hyperpolarize ↓ E5
M145T human SCN1A homo beta1(+) S1 GEFS+ ↓ depolarize, rise time↑ E7
D188V human SCN1A homo beta1(+) S2-S3 linker GEFS+ → ↓ E30
V1611F human SCN1A homo alpha1:beta1:beta2=10:1:1 S3 GEFS+ ↑ → hyperpolarize hyperpolarize ↓ E31
T875M rat scn1a homo alpha:beta=10:1 S4 GEFS+ → → ↓ E32
T875M* rat scn4a homo (-) S4 GEFS+ rise time↑ hyperpolarize E33
T875M human SCN1A homo alpha1:beta1:beta2=10:1:1 S4 GEFS+ ↑ → depolarize E28
R859C rat scn1a homo/hetero alpha1:beta1=10:1 S4 GEFS+ ↓ depolarize ↓ 18
R1657C human SCN1A homo alpha1:beta1:beta2=10:1:1 S5 GEFS+ → ↓ depolarize ↑ 28
V1353L human SCN1A homo alpha1:beta1:beta2=10:1:1 S5 GEFS+ ND 28
A1685V human SCN1A homo alpha1:beta1:beta2=10:1:1 S5 GEFS+ ND 28
R1657C human SCN1A homo alpha1:beta1:beta2=10:1:1 S5 GEFS+ ↓ 17
M1841T human SCN1A homo beta1,beta2,beta3,beta4,CaM C-terminal Interemediate ↓ 27
R1575C human SCN1A homo alpha1:beta1:beta2=10:1:1 S2 Interemediate ↑ → → → → E19
R1648H** rat scn4a homo beta(-) S4 Interemediate → rise time↑ hyperpolarize ↑ E34
R1648H rat scn1a homo alpha1:beta1=10:1 S4 Interemediate → → ↑ ↓ E32
R1648H human SCN1A homo alpha1:beta1:beta2=10:1:1 S4 Interemediate ↑ → E28
R1648H human SCN1A homo alpha1:beta1:beta2=10:1:1 S4 Interemediate ↑ 17
I1656M human SCN1A homo alpha1:beta1:beta2=10:1:1 S5 Interemediate → depolarize 28
T1709I human SCN1A homo alpha1:beta1:beta2=10:1:1 S5-S6 linker Interemediate ND E31
Y426N human SCN1A homo alpha1:beta1:beta2=10:1:1 I-II linker SRIEE ↓ hyperpolarize E35
N1011I human SCN1A homo alpha1:beta1:beta2=10:1:1 II-III linker SRIEE ↓ ↓ E31
F1808L human SCN1A homo alpha1:beta1:beta2=10:1:1 C-terminal SRIEE ↑ ↓ hyperpolarize hyperpolarize ↓ E31
T1909I human SCN1A homo alpha1:beta1:beta2=10:1:1 C-terminal SRIEE ↑ ↓ E35
T808S human SCN1A homo alpha1:beta1:beta2=10:1:1 S2 SRIEE ↑ ↓ E31
G177E human SCN1A homo alpha1:beta1:beta2=10:1:1 S2-S3 linker SRIEE ND E35
P1632S human SCN1A homo alpha1:beta1:beta2=10:1:1 S3-S4 linker SRIEE ↑ → hyperpolarize hyperpolarize ↓ E31
R1648C human SCN1A homo alpha1:beta1:beta2=10:1:1 S4 SRIEE ↑ depolarize hyperpolarize E36
I227S human SCN1A homo alpha1:beta1:beta2=10:1:1 S4 SRIEE ND E35
F1661S human SCN1A homo alpha1:beta1:beta2=10:1:1 S4-S5 linker SRIEE ↑ ↓ depolarize E36
F902C human SCN1A homo alpha1:beta1:beta2=10:1:1 S5 SRIEE ND E36
G1674R human SCN1A homo alpha1:beta1:beta2=10:1:1 S5 SRIEE ND E36
G1749E human SCN1A homo alpha1:beta1:beta2=10:1:1 S5-S6 linker SRIEE ↓ E36
R393H human SCN1A homo alpha1:beta1:beta2=10:1:1 S5-S6 linker SRIEE ND E35
H939Q human SCN1A homo alpha1:beta1:beta2=10:1:1 S5-S6 linker SRIEE ND E35
C959R human SCN1A homo alpha1:beta1:beta2=10:1:1 S5-S6 linker SRIEE ND E35
G979R human SCN1A homo alpha1:beta1:beta2=10:1:1 S6 SRIEE ND E31
L986F human SCN1A homo alpha1:beta1:beta2=10:1:1 S6 SRIEE ND 28
V983A human SCN1A homo alpha1:beta1:beta2=10:1:1 S6 SRIEE ↓ depolarize hyperpolarize ↓ E31
*Analyzed in scn4a T685M
** Analyzed in scn4a R1460H
→: no significant change
ND: not detected
homo: mutant channel is expressed homologously.
hetero: mutant channel was expressed with wild type channel heterogeneously
activation: voltage dependency of activation
innactivation: voltage dependency of innactivation