Biomedical Engineering Reference
In-Depth Information
Table 2 VGSC channelopathies
Mutated VGSC genes (subunits) Effects of channelopathies
References
SCN1A
(Na
v
1.1)
Epilepsy, migraine, neuropsychiatric disorders [
20
,
21
,
55
,
82
]
SCN2A
(Na
v
1.2)
Epilepsy
[
22
]
SCN3A
(Na
v
1.3)
Epilepsy, pain
[
25
,
40
,
41
]
SCN4A
(Na
v
1.4)
Myotonic syndromes
[
56
-
62
]
SCN5A
(Na
v
1.5)
Cardiovascular diseases, cancer
[
64
-
66
]
SCN8A
(Na
v
1.6)
Neurodegenerative diseases
[
73
-
76
]
SCN9A
(Na
v
1.7)
Epilepsy, pain, cancer
[
26
,
45
-
51
]
SCN10A
(Na
v
1.8)
Pain, neuropsychiatric disorders
[
41
,
45
,
80
,
81
]
SCN11A
(Na
v
1.9)
Pain
[
45
]
SCN1B
(Na
v
b
1)
Epilepsy, cardiac disorders
[
23
,
24
,
34
,
70
]
SCN2B
(Na
v
b
2)
Pain, cardiac disorders
[
42
,
70
]
SCN3B
(Na
v
b
3)
Cardiac disorders
[
43
,
70
]
SCN4B
(Na
v
b
4)
Cardiac disorders
[
70
]
as in heart, skeletal muscles and, recently, in certain types of cancer cells. Conse-
quently, a number of disorders affecting different areas of the human body and
ranging a wide spectrum of severity have been linked with mutated human VGSC
genes. The clinical manifestations of these disorders depend primarily on the
expression pattern of the mutant gene at the tissue level and the biophysical
character of VGSC dysfunction at the molecular level (Table
2
).
2.4.1 Epilepsy
Growing evidences suggest that abnormal VGSCs are involved in the pathophysi-
ology of both acquired and inherited epilepsy. Hundred mutations in VGSC genes
have been identified as responsible for inherited epileptic syndromes. Most epilep-
togenic mutations lie within
SCN1A
(encoding the Na
v
1.1
a
-subunit), whereas only
a few are in
SCN2A
(encoding the Na
v
1.2
a
-subunit), in
SCN1B
(encoding the
auxiliary
b
1-subunit), and possibly in
SCN3A
(encoding the Na
v
1.3
a
-subunit) and
SCN9A
(encoding the Na
v
1.7
-subunit) [
4
,
21
-
26
]. Na
v
1.1 mutations have been
associated with generalized epilepsy with febrile seizures plus (GEFS+); they are
missense mutations and are characterized by both a loss and a gain of function,
depending on the type of cells where they are expressed [
27
]. Nonetheless, a loss of
function has been found as the main effect induced by Na
v
1.1 mutations, which
leads to decreased Na
+
currents. For instance, severe myoclonic epilepsy of infancy
or Dravet syndrome (SMEI), a more serious form of epilepsy related to
SCN1A
mutations, is mostly caused by Na
v
1.1 loss of function [
28
], although it also
exhibits biophysical defects due to persistent Na
+
current [
29
]. The apparently
paradoxical link between VGSC loss of function and epilepsy could be explained
by the evidence that Na
v
1.1 is the predominant isoform in various types of inhibi-
tory interneurons, such as hippocampal GABAergic interneurons [
30
,
31
]. In fact, it
is possible that malfunctioning VGSCs compromise the network inhibition by
a
