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The Neurological Channelopathies
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Type Gene Channel Disease
Voltage
-gated
Na+ SCN4A subunit of NaV1.4 HyperK periodic paralysis
HypoK periodic paralysisParamyotonia congenita
K+ KCNJ2 subunit of Kir2.1 Andersens syndrome
KCNE3 Accessory subunit
MiRP2 (assembles with
KV3.4)
HypoK periodic paralysis
Ca2+ CACNA1S subunit of CaV1.1 HypoK periodic paralysisMalignant hyperthermia
RYR1 Ryanodine receptor
(sarcoplasmic channel)
Malignant hyperthermia
Central core disease
Cl- CLCN1 ClC1 Myotonia congenita
Ligand-
gated
Nicotinic
AChRs
CHRNA1 1 subunitCongenital myasthenic
syndromesCHRNB1 1 subunit
CHRND subunit
CHRNE subunit
1: Disorders of muscle
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2: Disorders of neurons
Type Gene Channel Disease
Voltage
-gated
Na+ SCN1A subunit of NaV1.1 GEFS+,SMEI
SCN2A subunit of NaV1.2 GEFS+
SCN1B 1 subunit
K+ KCNA1 subunit of Kv1.1 Episodic ataxia type 1
KCNQ2 M current BFNC
KCNQ3Ca2+ CACNA1A subunit of CaV2.1
(P/Q channel)
Familial hemiplegic migraine
Episodic ataxia type 2, SCA6
CACN1H subunit of CaV3.2(T-type channel)
Absence epilepsy
Cl- CLN2 ClC-2 Idiopathic generalised epilepsy
Ligand-
gated
Nicotinic
AChRs
CHRNA2 4 subunit AD nocturnal frontal lobe epilepsy
CHRNB4 2 subunit
GlycineR GLRA1 1 subunit Familial hyperekplexia
GABAAR GABRG2 2 subunit GEFS+
GABRA1 1 subunit Juvenile myoclonic epilepsy
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Type Gene Channel Disease
Gap-
junction
protein
GJB1 Connexin 32
(paranodal myelin)
X-linked Charcot-Marie-Tooth
disease
3: Disorders of glial cells
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Cooper & Jan 1999
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Voltage-gated channels
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Na+ channelopathies
Gene Channel Disease
Muscle SCN4A subunit of NaV1.4 Hyperkalaemic periodic paralysisHypokalaemic periodic paralysis
Paramyotonia congenita
Potassium-aggravated myotoniaMyotonia fluctuans
Myotonia permanens
etc
Neuronal SCN1A subunit of NaV1.1(somatic)
Generalised Epilepsy with Febrile
Seizures + (GEFS+),
Severe myoclonic epilepsy ofinfancy (SMEI)
SCN2A subunit of NaV1.2(axonal)
GEFS+
SCN1B 1 subunit
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Skeletal muscle Na+ channel NaV1.4
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Na+ channel activation, deactivation and inactivation
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Potassium-aggravated myotonia mutations affect single channel behaviour
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Most muscle Na+ channelopathies are:
dominantly inherited
associated with high serum [K+]
caused by impaired fast inactivation (mutations around III-IV linker, or
cytoplasmic receptor)
Mild impairment of fast inactivation myotonia
Severe impairment Na+ channels enter slow inactivated state
Hypokalaemic periodic paralysis can result from loss of function of Na+ channel
(mutations cluster in S4 voltage sensor)
Skeletal muscle Na+ channel NaV1.4 mutations
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Cannon, 1997
Computer model of myotonia and paralysis
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Na+ channelopathies
Gene Channel Disease
Muscle SCN4A subunit of NaV1.4 Hyperkalaemic periodic paralysisHypokalaemic periodic paralysis
Paramyotonia congenita
Potassium-aggravated myotoniaMyotonia fluctuans
Myotonia permanens
etc
Neuronal SCN1A subunit of NaV1.1(somatic)
Generalised Epilepsy with Febrile
Seizures + (GEFS+),
Severe myoclonic epilepsy ofinfancy (SMEI)
SCN2A subunit of NaV1.2(axonal)
GEFS+
SCN1B 1 subunit
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GEFS+: Generalised epilepsy with febrile seizures plus
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CNS Na+ channel mutations associated with GEFS+
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SCN1B mutation interferes
with the ability of the subunitto modulate channel gating
Wallace et al (1998)
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GEFS+-associated NaV1.1 mutations also interfere with fast inactivation
Lossin et al (2002)
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Remaining questions for Na+ channel mutations:
How do S4 mutations associated with hypokalaemic periodic paralysis cause membrane
depolarisation and [K+]?
What triggers seizure onset?
Why do some SCN1A mutations that affect other kinetic parameters cause epilepsy
Why is the phenotype so variable within GEFS+ families?
How do truncation mutations of SCN1A cause severe myoclonic epilepsy of infancy(SMEI)?
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Ca2+ channelopathies
Gene Channel Disease
Muscle CACNA1S subunit of CaV1.1 HypoK periodic paralysisMalignant hyperthermia
RYR1 Ryanodine receptor
(sarcoplasmic channel)
Malignant hyperthermia
Central core disease
Neuronal CACNA1A subunit of CaV2.1(P/Q-type channel)
Familial hemiplegic migraine
Episodic ataxia type 2
Spinocerebellar ataxia type 6
Absence epilepsy?CACNA1H subunit of CaV3.2
(T-type channel)
Absence epilepsy
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Ca2+ channel structure
2
1
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Skeletal muscle Ca2+ channel mutations
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Hypokalaemic periodic paralysis-associated mutations of CaV1.1 reduce
Ica, shift voltage sensitivity and slow channel kinetics
but why do they result in depolarisation and episodic paralysis?
Morrill & Cannon (1999)
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Malignant hyperthermia and central core disease are associated with mutations
of the ryanodine receptor gene RYR1
(CACNA1S mutations also found in MH)
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Ca2+ channelopathies
Gene Channel Disease
Muscle CACNA1S subunit of CaV1.1 HypoK periodic paralysisMalignant hyperthermia
RYR1 Ryanodine receptor
(sarcoplasmic channel)
Malignant hyperthermia
Central core disease
Neuronal CACNA1A subunit of CaV2.1(P/Q channel)
Familial hemiplegic migraine
Episodic ataxia type 2
Spinocerebellar ataxia type 6
Absence epilepsy?CACNA1H subunit of CaV3.2
(T-type channel)
Absence epilepsy
4 subunit mutations also reported in association with epilepsy/episodic ataxia
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Familial hemiplegic migraine:
Severe, autosomal dominant, associated with reversible weakness
Other associations: progressive cerebellar ataxia, coma, neuromuscular junction defect
Molecular pathogenesis: or current density left-shifted activation threshold
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Familial hemiplegic migraine: mouse knock-in model
P/Q-type Ca2+ channel-dependent neuromuscular transmission
van den Maagdenberg et al, 2004
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Familial hemiplegic migraine: mouse knock-in model
Cortical spreading depression
van den Maagdenberg et al, 2004
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Episodic ataxia type 2
Prolonged attacks of cerebellar inco-ordination
Associated with progressive cerebellar degeneration
Autosomal dominant
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Jouvenceau et al (2000)
EA2:premature stops, splice-site
mutations, mis-sense mutations
non-functional channel
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Spinocerebellar ataxia type 6
Site of CAG expansion
Normal allele: 4-18
SCA6: 19-30
Disease mechanism:
nuclear protein deposition?
altered channel density and activation threshold also reported
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Cl- channelopathies
Gene Channel Disease
Muscle CLCN1 ClC1 Myotonia congenitaAR (Beckers)
AD (Thomsens)
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ClC1:
homodimeric with two pores,
major determinant of resting membrane potential
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Membranepotential
Muscle fibres from myotonic goats:
repetitive discharges in response to small depolarising currents
myotonia results from loss of channel function
Adrian & Bryant (1974)
Control Myotonic
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Kubisch et al (1998)
Dominant or recessive behaviour of CLCN1 mutations is
reflected in co-expression studies
Dominant
Recessive
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Loss of function CLCN2
mutations in idiopathic
generalised epilepsy
Haug et al (2003)
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K+ channelopathies
Gene Channel Disease
Muscle KCNJ2 subunit of Kir2.1 Andersens syndrome
KCNE3 Accessory subunit MiRP2
(assembles with KV3.4)
HypoK periodic paralysis
Neuronal KCNA1 subunit of Kv1.1(axonal/presynaptic
delayed rectifier)
Episodic ataxia type 1Epilepsy, isolated
neuromyotonia
KCNQ2 M channel subunit Benign familial neonatal
convulsions
KCNQ3
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Muscle K+ channelopathies
Loss of function dominant negative effectAssociation with hypokalaemia poorly understood
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Episodic ataxia type 1
Brief attacks of cerebellar incoordination
Associated with neuromyotonia
Autosomal dominant
Pore
loop
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N C
Extracellular
Intracellular
+
loop
TranslationAssembly
Targeting
Kinetics
Permeation
Wt
R417s
top
Wt+R
417stop
0
0.5
1
Normalisedcurrentamplitude
WtWt+R417stop (scaled)
10 ms-100 mV
0 mV
* *
EA1:
Loss of function
Variable dominant negative effects
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Biervert et al (1998)
KCNQ2 mutation in BFNC causes decreased IK
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Wang et al (1998)
KCNQ2+KCNQ3 heteromultimers make IM channels
25% reduction in IM current is sufficient to cause disease (Schroeder et al (1998)
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Nicotinic receptor channelopathies
Gene Channel Disease
Muscle CHRNA1 1 subunit Congenital myasthenic syndrome
CHRNB1 1 subunit
CHRND subunit
CHRNE subunit
Neuronal CHRNA2 4 subunit AD nocturnal frontal lobe epilepsy
CHRNB4 2 subunit
Ni ti i t t th l j ti
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Nicotinic receptor mutations affect:
channel opening
receptor occupancy
expression of the fetal subunit
Nicotinic receptor at the neuromuscular junction
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Slow channel syndrome
Sine et al (1995)
Fast channel syndrome
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Fast channel syndrome
can be associated with congenital joint deformities (arthrogryposis multiplex)
Brownlow et al (2001)
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Nicotinic receptorchannelopathies
Gene Channel Disease
Muscle CHRNA1 1 subunit Congenital myasthenic syndrome
CHRNB1 1 subunit
CHRND subunit
CHRNE subunit
Neuronal CHRNA2 4 subunit AD nocturnal frontal lobe epilepsy
CHRNB4 2 subunit
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Amplitude Ach sensitivity Desensitisation gCa2+
4 S248F
4 L776ins3
4 S252L
2 V287M
CNS nicotinic receptor mutations: functional consequences
Bertrand et al (2002)
5 out of 5 mutations tested reduced Ca2+-dependent potentiation
Rodrigues-Pinguet et al (2003)
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Presynaptic 42 heteromultimeric nicotinic receptors enhance transmitter release
Gain of function may lower seizure threshold
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Glycine and GABAA receptor channelopathies
Receptor Gene Channel Disease
Neuronal Glycine GLRA1 1 subunit glycine R Familial hyperekplexia
GABAA GABRG2 2 subunit GABAAR GEFS+
GABRA1 1 subunit GABAAR Juvenile myoclonic epilepsy
Compound heterozygosity in
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Amino acid positions are quoted for the rat sequence
R252 E/Q and R271 E/Q - Langosch et. al., 1993R271L/Q - Shiang et. al., 1993; Langosch et. al., 1994I244N - Rees et. al., 1994Y279C - Shiang et. al., 1995K276E - Elmslie et. el., 1996; Lewis et. al., 1998Q266H - Milani et. al., 1996; Moorhouse et. al., 1999R271N/K/H - Lynch et. al., 1997; Langosh et. al., 1994P250T - Saul et. al., 1999R252H and R392H - Vergouwe et. al., 1999
Rea et al (2002)
Compound heterozygosity in
hyperekplexia
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Glycine receptor mutations reduce apparent affinity
K276E
wt
wt
K276E
Lewis et al (1998)
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GABAA receptors: 2 subunit plays a role in
synaptic targeting
benzodiazepine sensitivity ()
zinc sensitivity ()
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GABAA receptor2 subunit mutations associated with GEFS+:
surface expression
deactivation rate
Seizures arise because of loss of function
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GABAA receptor1 subunit mutation associated with JME
current density
EC50
Cossette et al 2002
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Neurological channelopathies:
affect both voltage- and ligand-gated channels
mainly autosomal dominant
loss of function in many cases
Other candidate disorders:
Common migraine
Primary epilepsy
Paroxysmal movement disorders
Conclusions