Jaarboek no. 89. 2010/2011 - Koninklijke Maatschappij voor ...

Natuurkundige voordrachten I Nieuwe reeks 89
Migraine: de ontrafeling van een complexe ziekte
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sible effects on cortical excitability. Given the lossof-function
phenotype identified by functional in
vitro assays, one would expect increased neuronal
excitability. In addition, because FHM2 is clinically
indistinguishable from FHM1, it would be interesting
to measure susceptibility to CSD in FHM2 mice.
C. NaV1.1 (FHM3)
Unlike CACNA1A and ATP1A2, in which a plethora of
FHM mutations have been identified, to date only
two mutations in SCN1A have been linked to FHM
(Fig. 3). The first mutation identified, Q1489K, has
been functionally studied. However, because of
well-known SCN1A cDNA instability in bacteria during
cloning procedures, the mutation was instead
introduced into the homologous NaV1.5 channel,
where it acted to accelerate recovery from inactivation.
Given that voltage-gated sodium channels
play a critical role in initiation and propagation of
action potentials, accelerated recovery from inactivation
would likely cause increased neuronal firing.
The complete picture is not likely to be so simple,
however. Studies have shown that, unlike NaV1.5, NaV1.1 is expressed primarily on inhibitory neurons,
where increased firing would lead to decreased
neuronal excitability. In addition, we can infer the
possible outcome of FHM3 mutations in NaV1.1 by
considering other missense mutations. For example,
de novo loss-of-function mutations in SCN1A have
been linked to severe myoclonic epilepsy in infancy
(SMEI). It was initially unclear why decreased function
of a channel that drives neuronal excitability
would lead to increased excitability, but this apparent
paradox was resolved when the Scn1a gene was
disrupted by gene targeting to generate a mouse
model for SMEI. Heterozygous Scn1a +/- mice exhibited
reduced sodium currents in their inhibitory
neurons, leading to hyperexcitability. A subsequent
knockin mouse model for SMEI showing epileptic
activity confirmed these results. The true test of the
effect of FHM3 mutations will await either in vitro
functional assays in NaV1.1 or the generation of an
FHM3 knockin mouse model. Until then, the available
knockout mouse may serve as a suitable model
to examine FHM and common migraine.
VII. FHM AS AN IONOPATHY: IDENTIFYING
A COMMON THEME AMONG FHM
SUBTYPES
The present challenge is in understanding how
mutations in three different genes encoding three
different proteins can cause similar (or even identical)
clinical outcomes. Currently, FHM (and perhaps
migraine in general) can best be described as a
generalized hyperexcitability due to impaired ion
homeostasis. Figure 4 shows a simplified schematic
of a synapse between an excitable presynaptic neuron
and a postsynaptic neuron, as well as input from
Figure 3
Schematic topographic drawing of the NaV1.1 subunit of the voltage-gated sodium channel encoded by the FHM3
gene SCN1A. The protein contains four repeating domains (I–IV), each consisting of six transmembrane helices (S1–S6).
The approximate locations of mutations linked to FHM are indicated. Amino acid positions refer to GenBank accession
number AB093548.