SCIENTIFIC

Genetic Disorders of Ion Channels

by Decha Enkvetchakul, MD

Ion channels play critical Abstract overview of human diseases that

roles in a wide variety of Ion channels play important are associated with mutations of
physiological processes, not roles in numerous physiological ion channels, and begins with three
limited to excitable cells. processes, including the control paradigms of ion channel function
of heart rate, propagation of and associated diseases: (1) generation
the nerve impulse, and insulin of the action potential and Long QT
secretion. Abnormal functioning syndrome, (2) salt reabsorption in
of ion channels can cause disease. the kidney and Bartter’s syndrome,
This article presents an overview and (3) the regulation of insulin
of the diseases in humans that secretion and diabetes/congenital
are a result of mutations in ion hyperinsulinism. Diseases grouped by
channels. channel type will also be presented.
Diseases that are the result of
Introduction acquired altered ion channel function
Movement of charged molecules are not discussed.
in and out of the cell is often
energetically unfavorable due to the Long QT Syndrome
presence of the cell membrane. Ion The cardiac action potential
channels are membrane-intrinsic is the result of a complex interplay
proteins that form water-filled pores of currents through ion channels.
through the membrane, providing Some of the major currents that
a pathway for ions to cross. Many underlie the cardiac action potential
channels are able to control the flow are shown in Figure 1A. Initially,
of ions in response to a variety of influx of sodium ions (INa) through
signals, and act as critical control activated sodium channels depolarizes
points in a vast array of physiological the membrane, forming the rapid
phenomena, e.g. the electrical activity upward phase. Sodium channels
of neurons and muscles that allow us then rapidly inactivate, but the
to think and move, and the secretion depolarized cell membrane activates
of insulin necessary for glucose voltage-gated potassium and calcium
homeostasis. It is not surprising that channels. Calcium influx through
Decha Enkvetchakul, MD, is an Assistant
Professor in the Department of mutation of genes coding for ion calcium channels tends to depolarize
Pharmacological and Physiological Science channel proteins result in disease. the membrane, while potassium
at the Saint Louis University School of
Medicine. This article presents a brief (and efflux through potassium channels
Contact: denkvetc@slu.edu therefore necessarily incomplete) tends to repolarize the membrane.

270  July/August 2010  107:4 Missouri Medicine

These two opposing effects create syndrome is due to mutations
the plateau of the cardiac action in CACNA1C (calcium channel Figure 1
The cardiac action potential and surface ECG.
potential. Repolarization occurs with CaV1.2, ICa in Fig 1A) that Some of the major ionic currents involved are
closure of the calcium channels. In cause delayed channel closure, indicated.
an ECG, ventricular depolarization manifested as LQT along with
is represented by the QRS syndactyly, autism, and facial A ICa
complex, while the T wave is due to dysmorphisms. IKr
repolarization (See Figure 1B). In contrast, loss-of- IKs
Potassium currents also assist function mutations in NaV1.5, INa
in repolarization of the cardiac cell or gain-of-function mutations IK1
membrane, and include the slowly in KV7.1 or KV11.1 lead to
activating potassium current (IKs) due early repolarization associated
to the potassium channel complex with arrhythmias, and can be
KV7.1(KCNQ1) + minK(KCNE1), seen in Brugada’s and short
B
and the rapidly activating potassium QT syndrome1.
current (IKr) through KV11.1 (KCNH2)
+ MiRP1 (KCNE2)1. Decreased K Bartter’s Syndrome
currents as a result of mutations Sodium reabosorption in QT
in these K channel complexes can the thick ascending loop of Interval
cause a prolongation of the action Henle occurs in cotransport
potential and lengthening of the QRS with K+ and Cl+ ions
to T wave interval on an ECG (Fig through the NaK2Cl Figure 2
1B), manifesting as Long QT (LQT) cotransporter (See Schematic of ion channels and transporters involved
syndrome. Patients with LQT are in sodium reabsorption in the distal loop of Henle.
Figure 2). The luminal
predisposed to sudden death due to concentration of K is
cardiac arrhythmias and Torsades de many fold lower than
Pointes, particularly under stressful Na, and continued NKCC2
situations that increase adrenergic reabsorption 2Cl-
tone. Profound deafness can be seen requires recycling Na+ 2K+
+ ATP
in patients with LQT due to mutations of K back into the K 3Na+
in KV7.1, as it is necessary for hair cell lumen through Kir1
development in the inner ear. channels. Na and Cl
K+
CLC-Kb
The potassium channel ions then exit the cell Cl
Kir2(KCNJ2), also plays an important through the 3Na/2K Kir1
role in repolarization (See Figure ATPase and CLC-Kb Barttin
1A, IK1). Mutations in this channel channels, both found Lumen
are associated with Andersen-Tawil in the basolateral
syndrome1, characterized by a milder membrane. Mutations
QT prolongation, periodic paralysis, in genes that code Mutations in the CLC-Kb channels
cardiac dysrhythmias and dysmorphic for Kir1 resulting in a loss of K that reduce Cl- efflux result in classic
features. recycling is associated with the severe Bartter’s syndrome2, a milder form
Mutations that delay closure antenatal form of Bartter’s syndrome2, that is typically diagnosed in school-
of calcium and sodium channels, characterized by polyhydramnios, age children. Bartter’s may also be
prolonging depolarization, are also premature delivery, and a failure to the result of a mutation in Barttin,
associated with LQT syndrome1, and thrive. Neonates develop severe salt a chaperone protein that is required
include activating mutations in the wasting, hypokalemia, metabolic for proper trafficking of the CLC-
SCN5A gene (sodium channel NaV1.5) acidosis, hyperprostaglandinemia, Kb channel to the membrane2. In
that cause a persistent sodium and hypercalciuria that can lead to addition, Barttin is required for
current in the plateau phase. Timothy osteopenia and nephrocalcinosis. trafficking of ClC-Ka and ClC-Kb

107:4 Missouri Medicine  July/August 2010  271

 A polymorphism of the Kir6.2
Figure 3 gene (E23K) that results in a mild
Paradigm of insulin secretion from the pancreatic β-cell.
decrease in sensitivity to inhibition
KATP by ATP may be associated with an
Inhibition increased risk in developing type II
Kir6.2 diabetes3.
SUR

Membrane +
Other Channelopathies,
K
Depolarization Grouped by Ion Channel Type

Voltage-Gated Potassium (KV)

[Ca2+] ATP Channels
MgADP
2+ Glucose In addition to cardiac arrhythmias
Ca (discussed above), KV channels are
Vesicle
Calcium Channel Fusion associated with syndromes that
Activation affect the neuron. Mutations in
KV1.1(KCNA1)2 are associated with
episodic ataxia (EA), and reduce K
Insulin conductance, leading to prolonged
Secretion action potentials and increased cell
excitability. EA patients have bouts of
ataxia and loss of balance, provoked
channels in the inner ear, and loss of the ATP/ADP ratio decreases, KATP by stress, startle, or heavy exertion
Barttin function results in deafness. channels open, and insulin secretion such as exercise.
is inhibited. KCNQ2 and KCNQ3 encode for
Regulation of In this paradigm, the KATP proteins that heteromultimerize
Insulin Secretion channel plays a key role in the into a K channel that underlies
The mechanism of insulin regulation of insulin secretion. the M-current2. This K current is
secretion in response to blood Loss of KATP channel activity would important in controlling excitability
glucose levels is well characterized3 be expected to cause persistant of many neurons. Benign familial
(See Figure 3). Elevations of blood membrane depolarization, and neonatal convulsions is associated
glucose (such as that occurring after hypersecretion of insulin. Congenital with mutations resulting in increased
eating) increases ATP and decreases hyperinsulinism is a rare disorder neuronal excitability due to decreased
ADP in the pancreatic -cell due to characterized by inappropriate M-currents. Patients have tonic-
glucose metabolism. KATP channels, insulin secretion and hypoglycemia clonic seizures within the first seven
which are inhibited by ATP and that can be very severe. Loss-of- days of life. Seizures spontaneously
activated by ADP, close in response function mutations in the subunits remit after about three months,
to the increase in ATP to ADP ratio. that form the KATP channel (Kir6.2 apparently due to compensation by
KATP channels are responsible for KCNJ11 and SUR1 ABCC8) have been other neuronal currents, but patients
maintaining the resting membrane found in patients with congenital are more susceptible to developing
potential, and closure of these hyperinsulinism3, 4. In contrast, seizures later in life.
channels leads to membrane patients with mutations that increase The BK (KCNMA) channel,
depolarization and activation of KATP channel activity display an a calcium activated K channel
voltage-dependent calcium channels, undersecreting phenotype and widely expressed in the central
followed by a rise of intracellular hypoinsulinemia called neonatal nervous system, is associated with a
calcium, which then stimulates diabetes. These patients develop syndrome of generalized epilepsy and
insulin secretion. Conversely, when diabetes before 6 months of age paroxysmal dyskinesia. Mutations
glucose concentrations decrease, that may be transient or permanent. increase the activity of this K channel5.

272  July/August 2010  107:4 Missouri Medicine

Voltage-Gated Sodium (NaV) tonic–clonic seizures. Mutations in Epithelial Sodium Channels (ENaC)
Channels SCN9A(NaV1.7) are associated with ENaC is located in the apical
In muscle, mutations that cause familial primary erythermalgia, a membrane of epithelial cells of
persistant activity of the voltage- rare autosomal dominant disorder the lung, kidney, and colon, and
gated sodium channel NaV1.4 characterized episodes of redness, are important in the transcellular
(SCN4A) have been associated with swelling, and painful burning in the transport of sodium ions. Liddles
cell hyperexcitability, manifested as extremities. syndrome is a rare form of
repetitive action potential generation hypertension associated with
and impaired muscle relaxation Voltage-Gated Calcium (CaV) hyperactive ENaC channels in
(myotonia), as seen in paramyotonia Channels the distal nephron. Patients have
congenita and potassium-aggravated In response to depolarization of severe hypertension at an early age,
myotonias6. Depending on the the sarcomeric membrane, calcium hypokalemia, metabolic acidosis,
size of the Na currents, excessive channels of the T-tubules open and low serum aldosterone levels.
depolarization and paralysis can allowing entry of calcium and muscle Mutations found in Liddles block
also occur, as seen in hyperkalemic contraction. Mutations that decrease ubiquitination of ENaC12 so that
periodic paralysis7. Symptoms often the activity of CaV1.1(CACNA1S), it is no longer properly degraded,
can be triggered by high potassium expressed in the transverse tubules leading to increased sodium
diets, presumably through raising of skeletal muscle cells, can cause reabsorption and hypertension.
serum potassium levels which leads HypoPP7. CaV1.1 mutations Treatment by blockade of the ENaC
to a mild depolarization of muscle associated with HypoPP reduce with amiloride or triamterene is
membrane and further enhancing activation of the channel. Similar to effective. Conversely, loss-of-function
sodium channel activity. In contrast, the Na channel associated HypoPP, mutations in ENaC subunits (genes
mutations that decrease NaV1.4 hypokalemia worsens the condition SCNN1A, SCNN1B, and SCNN1G) are
activity have been associated with by hyperpolarizing the cell membrane associated with autosomal recessive
hypokalemic periodic paralysis and making it more difficult to pseudohypoaldosteronism Type-1.
(HypoPP)7. Episodes of paralysis activate the calcium channel. Most of the mutations are predicted
can be triggered by events that lower Mutations in the CACNA1F to result in non-functional channels,
serum potassium, which can occur (CaV1.4, highly expressed in the as a result of frameshift or early stop
after high carbohydrate meals with retina) is associated with incomplete codons12. Patients present with salt-
elevated insulin levels, or under congenital stationary night blindness. wasting, hyperkalemia, metabolic
stress with release of adrenaline, Patients with this disorder have acidosis, and high serum aldosterone
resulting in hyperpolarization of the night blindness and decreased levels.
membrane and making activation of visual acuity, thought due to defects
these mutant channels even more in photoreceptor transduction. Chloride Channels (ClC)
difficult. Mutations result in either non- Mutations in ClC-1 have
In neurons, mutations of functional channels or shift the been associated with congenital
voltage gated sodium channels voltage-dependence of opening to myotonias7, 13, characterized by
have complex effects, and the same more hyperpolarized potentials. stiffness due to slow relaxation of
mutation can lead to both increased Familial hemiplegic migraine the muscles after contraction. ClC-1
and decreased cell excitability8. with aura associated with hemiparesis, is almost exclusively expressed in
Mutations in SCN1A(NaV1.1), episodic Ataxia type-2, and skeletal muscle and is important
SCN2A(NaV1.2), and SCN1B (sodium- spinocerebellar ataxia type-6 are in repolarization and maintanence
channel -subunit), have been all associated with mutations in the of the resting membrane potential.
associated with a variety of seizure calcium channel gene, CACNA1A Mutations that lead to truncated
disorders including generalized (CaV2.1, expressed heavily in the proteins are seen in the recessive form
epilepsy with febrile seizures plus, cerebellar Purkinje cells)9-11. They (Becker’s), while mutant subunits
severe myoclonic epilepsy of infancy, are all associated with cerebellar that are able to interact with normal
and the syndrome of intractable degeneration but differ in rate and subunits and interfere with their
childhood epilepsy with generalized extent of disease progression. function are seen in the autosomal

107:4 Missouri Medicine  July/August 2010  273

dominant form (Thomsen’s). These SCS, mutant AChR channels have Aquaporins
mutations result in hyperexcitable increased activity and longer channel The autosomal recessive and
muscle cells. Findings in Thomsen’s openings, producing a prolonged dominant forms of nephrogenic
are noticeable at birth or in early depolarization of the muscle cell diabetes insipidus (NDI) are
childhood, and are progressive. membrane. Excessive depolarization associated with loss of function
Muscle hypertrophy is a common results in inactivation of sodium mutations in the aquaporin 2 channel
sign. channels, accounting for the muscle (AQP2)16. Multiple disease-causing
weakness. In contrast to SCS, nAChR AQP2 mutations have been identified.
Cyclic-Nucleotide Gated (CNG) channels either fail to open or close In autosomal recessive NDI, the
Channels too quickly in FCS. Mutations in mutations result in misfolded
CNG channels of the retina FCS appear to decrease binding aquaporin proteins that are retained
are critical in visual transduction. affinity of acetylcholine and the in the endoplasmic reticulum.
In the dark, high levels of cGMP ability of the channel to open. In contrast, autosomal dominant
activate CNG channels, allowing mutations result in subunits that
calcium influx and stimulating Glycine Receptor are able to associate with normal
neurotransmitter release. Light Mutations in this channel subunits, resulting in mistrafficking
activates cGMP phosphodiesterase, are associated with a very rare or loss of function of the heteromeric
leading to closure of CNG channels disorder called Startle Disease13 channel. A small number of people
and shutting off neurotransmitter This autosomal dominant disease have been identified with severe
release. Mutations of the rod causes stiffening of the muscles or total deficiency in aquaporin-1
cell CNG channel (CNGA1) are in response to startling. Severe (AQP1)16, but they are generally
associated with retinitis pigmentosa responses can occur, along with healthy with a mild defect in the
(RP)14. Patients with RP suffer injuries as the rigidity prevents urinary concentrating ability.
from night blindness, progressive patients from reaching out when
reduction of the visual field, and falling. Similar symptoms can be Connexins (Cx)
abnormal pigmentation of the retina. seen with strychinine poisoning, a Connexin subunits assemble
Mutations in CNGA3 and CNGB3, glycine channel inhibitor2. Mutations into gap junctions providing
both encoding for CNG channels found in this disease decrease the electrical and metabolic coupling
in cone cells, are associated with activity of the glycine receptor and between cells. Numerous human
achromatopsia14, characterized by the its inhibitory actions, important disorders associated with mutations
inability to perceive color and poor for normal muscle tone and motor in connexins are known, and are
visual acuity. neuron firing patterns. Treatment grouped into seven major categories:
includes agonists of GABA chloride
neuropathic or myelin disorders,
Nicotinic Cetylcholine Receptor channels (e.g. clonazepam),
nonsyndromic and syndromic
(nAChR) Channels presumably by compensating for the
deafness, skin diseases, cataracts,
nAChR are cation selective decreased chloride current through
oculodentodigital dysplasia, and
channels that are important in the glycine receptor.
neuromuscular signaling. Binding of idiopathic atrial fibrillation17.
acetylcholine activates these channels Ionotropic Gamma-Aminobutyric Charcot Marie Tooth is an X-linked
causing membrane depolarization Acid (GABAA) Receptors disorder associated with mutations in
of the postsynaptic neuromuscular Like glycine receptors, GABAA Cx32 channels, which are important
junction and muscle contraction. receptors are chloride selective in delivery of metabolites between
Mutations in the nAChR are channels, and have an inhibitory the layers of the myelin sheath
associated with two syndromes, the action in the brain. Rare mutations formed by Schwann cells. Mutations
Slow Channel Syndrome (SCS) and of the GABRA1, GABRG2 or GABRD in Cx26, Cx30, and Cx31 are
the Fast Channel Syndrome(FCS)7. gene, encoding the 1,2 or  associated with deafness and skin
Patients usually present at birth subunit of the GABA receptor disorders that can occur separately or
with muscle weakness, rapid fatigue, have been associated with seizure together. Cx46 and Cx50 are found
and progressive muscle atrophy. In disorders13, 15. in the lens and mutations may result

274  July/August 2010  107:4 Missouri Medicine

in congenital cataracts. Mutations encode for ion channels underlie
of Cx40 have been linked to atrial many human diseases. A better
fibrillation. understanding of how these channels
CLASSIFIED
function, both on a molecular and
TRP Channels cellular level, will undoubtedly ED PHYSICIAN
The TRP channels are a family provide a rational framework to help OPPORTUNITY
of relatively non-selective cation develop targeted treatments for many • Live and play where history
channels. TRP channels are expressed of these diseases. and heritage come alive.
throughout the body and respond
to a wide variety of stimuli. TRPC6 References • Dexter, MO: 12.6K Volume,
is expressed in the podocytes of the 1. Morita, H., J. Wu, and D.P. Zipes, The QT BC/BE in EM or PC. What’s
nephron, mutations in this channel
syndromes: long and short. Lancet, 2008. 372(9640): important to YOU is what
p. 750-63.
matters to US…Excellent
is associated with focal segmental 2. Ashcroft, F.M., Ion Channels and Diseases.
2000: Academic Press. Compensation, Paid
glomerulosclerosis18, a disease Malpractice w/ Tail,
3. Koster, J.C., M.A. Permutt, and C.G. Nichols,
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renal failure. The mechanism by 4. Huopio, H., et al., K(ATP) channels and • Contact Lily Santiago
which mutations cause disease is insulin secretion disorders. Am J Physiol Endocrinol (800) 815-8377 x 2261
unknown. Metab, 2002. 283(2): p. E207-16. lsantiago@hppartners.com
5. Du, W., et al., Calcium-sensitive potassium
Hypomagnesemia with secondary or visit
channelopathy in human epilepsy and paroxysmal
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the nephron and in the gut, and is Muscle channelopathies and critical points in
important for transcellular magnesium functional and genetic studies. J Clin Invest, 2005.
& PHYSICIAN
absorption. It is often associated with 115(8): p. 2000-9. OPPORTUNITIES
severe hypocalcemia that can present
8. Waxman, S.G., Channel, neuronal and clinical • Located in the great state
function in sodium channelopathies: from genotype
of Missouri.
as convulsions and spasms in early to phenotype. Nat Neurosci, 2007. 10(4): p. 405-9.
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of parathyroid hormone. Treatment 10. Kordasiewicz, H.B. and C.M. Gomez,
What’s important to YOU
includes high doses of magnesium Molecular pathogenesis of spinocerebellar ataxia type
6. Neurotherapeutics, 2007. 4(2): p. 285-94. is what matters to US…
salts. 11. de Vries, B., et al., Systematic analysis of three Excellent Compensation and
The PKD2 gene encodes for the FHM genes in 39 sporadic patients with hemiplegic Paid Malpractice w/ Tail.
TRPP2 channel, critical in calcium migraine. Neurology, 2007. 69(23): p. 2170-6.
12. Riepe, F.G., Clinical and molecular features of
signal transduction and regulated type 1 pseudohypoaldosteronism. Horm Res, 2009.
• Contact Lily Santiago
by polycystin-1 (PKD1). Loss-of- 72(1): p. 1-9. (800) 815-8377 x 2261
function mutations in either of these 13. Planells-Cases, R. and T.J. Jentsch, Chloride lsantiago@hppartners.com
channelopathies. Biochim Biophys Acta, 2009. or visit
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dominant polycystic kidney disease. 14. Biel, M. and S. Michalakis, Function and
www.hppartners.com.
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likely a major cause19. 2007. 35(3): p. 266-77. 18. Montell, C., The TRP superfamily of cation
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