Ion Channels and Human Disorders

Abstract

The human channelopathies are a rapidly expanding group of primarily genetic conditions. They are characterised by dysfunction of membrane‐bound glycoproteins (ion channels). Several neurological and general medical disorders have been shown to be owing to underlying ion‐channel dysfunction and genetic analysis is now often a routine clinical practice. These disorders exhibit extensive phenotypic and genetic heterogeneity with many distinct diseases caused by dysfunction of the same channel by differing mechanisms. With the advent of the next‐generation sequencing, we are discovering even greater genetic heterogeneity and our understanding of the mechanisms behind these diseases continues to extend as more functional analysis is performed and new techniques are developed. In the future, this will lead to the identification of better targeted treatments for these diseases.

Key Concepts

  • Channelopathies are commonly owing to mutations in functionally important regions of either pore‐forming or auxiliary channel subunits resulting in episodic disorders.
  • Mutations often cause disease by altering channel gating, voltage dependence or channel assembly and now there is also evidence for effects in posttranslational modification.
  • Channelopathies are now understood to present either with intermittent symptoms which may completely recover, have a secondary progression or may be a severe primary progressive disease. The location and type of the mutation often influence this.
  • Genetic heterogeneity is very common amongst the channelopathies and is likely to increase with the use of modern genetic analysis.
  • Channelopathies, such as myotonia congenita, have extensive phenotypic variability even within a single pedigree, making it difficult to predict and give accurate genetic counselling.

Keywords: channelopathy; myotonia; migraine; epilepsy; episodic ataxia; spinocerebellar ataxia

Figure 1. Schematic diagram demonstrating the main components of an ion channel. (a) Pore‐forming subunit; (b) aqueous pore; (c) ion selectivity filter; (d) voltage sensor; (e) gating mechanism and (f) auxiliary subunits.
Figure 2. (a) Representation of the membrane topology of the chloride channel. (b) Schematic diagram of the double‐barrelled ClC‐l channel. This shows two separate pores formed by each ClC‐l subunit.
Figure 3. (a) Membrane topology of the α subunit of the voltage‐gated calcium channel. Each domain (DI–IV) consists of six transmembrane segments (S1–6). The fourth segment (S4) in each domain acts as a voltage sensor. (b) Locations of EA2 (green circles), FHM (red circles) and SCA6 (blue) mutations in CACNA1A. (c) Representation of the P/Q‐type calcium channel with the central pore‐forming subunit (α1) and its auxiliary subunits (α2, β, γ and δ).
Figure 4. Tetramerisation of Kv1.1 subunits (α) with associated β subunits forming the voltage‐gated potassium channel.
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References

Ackerman MJ and Clapham DE (1997) Ion channels: basic science and clinical disease. New England Journal of Medicine 336: 1575–1586.

Ashcroft FM (2000) Ion Channels and Disease. London: Academic Press.

Becker PE (1977) Myotonia Congenita and Syndromes Associated with Myotonia. Stuttgart: Georg Thieme Verlag.

Beckh S and Pongs O (1990) Members of the RCK potassium channel family are differentially expressed in the rat nervous system. EMBO Journal 9: 777–782.

Bendahhou S, Donaldson MR, Plaster NM, et al. (2003) Defective potassium channel Kir2.1 trafficking underlies Andersen–Tawil syndrome. Journal of Biological Chemistry 278: 51779–51785.

Brandt T and Strupp M (1997) Episodic ataxia type 1 and 2 (familial periodic ataxia/vertigo). Audiology and Neurotology 2: 373–383.

Bretschneider F, Wrisch A, Lehmann‐Horn F and Grissmer S (1999) Expression in mammalian cells and electrophysiological characterization of two mutant Kv1.1 channels causing episodic ataxia type 1 (EA‐1). European Journal of Neuroscience 11: 2403–2412.

Browne DL, Gancher ST, Nutt JG, et al. (1994) Episodic ataxia–myokymia syndrome is associated with a point mutation in the human potassium channel gene, KCNA1. Nature Genetics 8: 136–140.

Brunt ER and van Weerden TW (1990) Familial paroxysmal kinesogenic ataxia and continuous myokymia. Brain 113: 1361–1382.

Cannon SC (2010) Voltage‐sensor mutations in channelopathies of skeletal muscle. Journal of Physiology 588 (Pt 11): 1887–1895.

Chen Y, Lu J, Pan H, et al. (2003) Association between genetic variation of CACNA1H and childhood absence epilepsy. Annals of Neurology 54: 239–243.

Colding‐Jørgensen E (2005) Phenotypic variability in myotonia congenita. Muscle & Nerve 32 (1): 19–34.

Davies NP and Hanna MG (2001) The neurological channelopathies. In: Scolding NJ (ed) Contemporary Treatments in Neurology, pp. 400–440. Oxford, UK: Butterworth‐Heinemann.

De Fusco M, Marconi R, Silvestri L, et al. (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nature Genetics 33 (2): 192–196.

Denier C, Ducros A, Vahedi K, et al. (1999) High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology 52: 1816–1821.

Dichgans M, Freilinger T, Eckstein G, et al. (2005) Mutation in the neuronal voltage‐gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366: 371–377.

Donaldson MR, Jensen JL, Tristani‐Firouzi M, et al. (2003) PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology 60: 1811–1816.

Doyle DA, Morais Cabral J, Pfuentzner RA, et al. (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280: 69–77.

Du X, Wang J, Zhu H, et al. (2013) Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6. Cell 154: 118–133. DOI: 10.1016/j.cell.2013.05.059.

Ducros A, Denier C, Joutel A, et al. (1999) Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. American Journal of Human Genetics 64: 89–98.

Ducros A, Denier C, Joutel A, et al. (2001) The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. New England Journal of Medicine 345: 17–24.

Dutzler R, Campbell EB, Cadene M, et al. (2002) X‐ray structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion selectivity. Nature 415: 287–294.

Elliott MA, Peroutka SJ, Welch S and May EF (1996) Familial hemiplegic migraine, nystagmus and cerebellar atrophy. Annals of Neurology 39: 100–106.

Epi4K Consortium (2016) De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. American Journal of Human Genetics 99: 287–298.

Eunson LH, Rea R, Zuberi SM, et al. (2000) Clinical, genetic and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability. Annals of Neurology 48: 647–656.

Ferrick‐Kiddie EA, Rosenthal JJ, Ayers GD and Emeson RB (2017) Mutations underlying Episodic Ataxia type‐1 antagonize Kv1.1 RNA editing. Scientific Reports 7: 41095. DOI: 10.1038/srep41095.

Fialho D, Schorge S, Pucovska U, et al. (2007) Chloride channel myotonia: exon 8 hot‐spot for dominant‐negative interactions. Brain 130 (part 12): 3265–3274.

Fletcher CF and Frankel WN (1999) Ataxic mouse mutants and molecular mechanisms of absence epilepsy. Human Molecular Genetics 8: 1907–1912.

Graves TD, Cha YH, Hahn AF, et al. (2014) CINCH investigators. Episodic ataxia type 1: clinical characterization, quality of life and genotype‐phenotype correlation. Brain 137 (Pt 4): 1009–1018. DOI: 10.1093/brain/awu012.

Greenburg DA (1997) Calcium channels in neurological disease. Annals of Neurology 42: 275–282.

Hans M, Luvisetto S, Williams ME, et al. (1999) Functional consequences of mutations in the human α‐1A calcium channel subunit linked to familial hemiplegic migraine. Journal of Neuroscience 19: 1610–1619.

Hille B (1992) Ion Channels of Excitable Membranes, 2nd edn. Sunderland, MA: Sinauer Associates.

Imbrici P, Jaffe SL, Eunson LH, et al. (2004) Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain 127: 2682–2692.

Imbrici P, D'Adamo MC, Kullmann DM and Pessia M (2006) Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4‐1.1/Kvbeta1.1 and Kv1.4‐1.1/Kvbeta1.2. European Journal of Neuroscience 24 (11): 3073–3083.

Ishikawa K, Fujigasaki H, Saegusa H, et al. (1999) Abundant expression and cytoplasmic aggregations of alpha‐1A voltage‐dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6. Human Molecular Genetics 8: 1185–1193.

Jen JC, Wan J, Palos TP, Howard BD and Baloh RW (2005) Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 65 (4): 529–534.

Jeng CJ, Chen YT, Chen YW and Tang CY (2006) Dominant‐negative effects of human P/Q‐type Ca2+ channel mutations associated with episodic ataxia type 2. American Journal of Physiology. Cell Physiology 290: C1209–C1220.

Jodice C, Mantuano E, Veneziano L, et al. (1997) Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Human Molecular Genetics 6: 1973–1978.

Koch MC, Steinmeyer K, Lorenz C, et al. (1992) The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257: 797–800.

Kokunai Y, Nakata T, Furuta M, et al. (2014) A Kir3.4 mutation causes Andersen–Tawil syndrome by an inhibitory effect on Kir2.1. Neurology 82 (12): 1058–1064.

Kubodera T, Yokota T, Ohwada K, et al. (2003) Proteolytic cleavage and cellular toxicity of the human alpha1A calcium channel in spinocerebellar ataxia type 6. Neuroscience Letters 341 (1): 74–78.

Labrum RW, Rajakulendran S, Graves TD, et al. (2009) Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing. Journal of Medical Genetics 46 (11): 786–791.

Lipicky RJ and Bryant SH (1966) Sodium, potassium and chloride fluxes in intercostal muscle from normal goats and goats with hereditary myotonia. Journal of General Physiology 50: 89–111.

Lorenz C, Pusch M and Jentsch TJ (1996) Heteromeric CLC chloride channels with novel properties. Proceedings of the National Academy of Sciences of the United States of America 93: 13362–13366.

Mantuano E et al. (2010) Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2. Journal of the Neurological Sciences 291: 30–36. DOI: 10.1016/j.jns.2010.01.010.

Matthews E, Labrum R, Sweeney MG, et al. (2009) Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 72: 1544–1547.

Miceli F, Soldovieri MV, Ambrosino P, et al. (2013) Genotype‐phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. Proceedings of the National Academy of Sciences of the United States of America 110: 4386–4391.

Miller TM, Dias da Silva MR, Miller HA, et al. (2004) Correlating phenotype and genotype in the periodic paralyses. Neurology 63: 1647–1655.

Ophoff RA, Terwindt GM, Vergouwe MN, et al. (1996) Familial hemiplegic migraine and episodic ataxia type‐2 are caused by mutations in the calcium channel gene CACNL1A4. Cell 87: 543–552.

Plaster NM, Tawil R, Tristani‐Firouzi M, et al. (2001) Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell 105: 511–519.

Rajakulendran S, Schorge S, Kullmann DM and Hanna MG (2007) Episodic ataxia type 1: a neuronal potassium channelopathy. Neurotherapeutics 4 (2): 258–266.

Raja Rayan DL, Haworth A, Sud R, et al. (2012) A new explanation for recessive myotonia congenita: exon deletions and duplications in CLCN1. Neurology 78 (24): 1953–1958.

Ronen GM, Rosales TO, Connolly M, Anderson VE and Leppert M (1993) Seizure characteristics in chromosome 20 benign familial neonatal convulsions. Neurology 43: 1355–1360.

Rudel R (1990) The myotonic mouse: a realistic model for the study of human recessive generalized myotonia. Trends in Neurosciences 13: 1–3.

Russell MB and Ducros A (2011) Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. Lancet Neurology 10: 457–470.

Schartner V, Romero NB, Donkervoort S, et al (2017) Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta Neuropathologica 133: 517–533. DOI: 10.1007/s00401-016-1656-8.

Schroeder BC, Kubisch C, Stein V and Jentsch TJ (1998) Moderate loss of function of cyclic‐AMP‐modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature 396: 687–690.

Smart SL, Lopanstev V, Zhang CL, et al. (1998) Deletion of the Kv1.1 potassium gene causes epilepsy in mice. Neuron 20: 809–819.

Suominen T, Schoser B, Raheem O, et al. (2008) High frequency of co‐segregating CLCN1 mutations among myotonic dystrophy type 2 patients from Finland and Germany. Journal of Neurology 255: 1731–1736.

Terwindt GM, Ophoff RA, Haan J, et al. (1998) Variable clinical expression of mutations in the P/Q‐type calcium channel gene in familial hemiplegic migraine. Neurology 50: 1105–1110.

Tinel N, Lauritzen I, Chouabe C, Lazdunski M and Borsotto M (1998) The KCNQ2 potassium channel splice variants, functional and developmental expression: brain localization and comparison with KCNQ3. FEBS Letters 438: 171–176.

Tristani‐Firouzi M, Jensen JL, Donaldson MR, et al. (2002) Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). Journal of Clinical Investigation 110: 381–388.

Wang HS, Pan Z, Shi W, et al. (1998) KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M‐channel. Science 282: 1890–1893.

Weckhuysen S, Mandelstam S, Suls A, et al. (2012) KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Annals of Neurology 71: 15–25.

Yue Q, Jen JC, Nelson SF and Baloh RW (1997) Progressive ataxia due to a missense mutation in a calcium channel gene. American Journal of Human Genetics 61: 1078–1087.

Zhuchenko O, Bailey J, Bonnen P, et al. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A voltage‐dependent calcium channel. Nature Genetics 15: 62–69.

Zoghbi HY (1996) The expanding world of ataxins. Nature Genetics 14: 237–240.

Zuberi SM, Eunson LH, Spauschus A, et al. (1999) A novel mutation in the human voltage‐gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain 122: 817–825.

Further Reading

Cannon SC (2006) Pathomechanisms in channelopathies of skeletal muscle and brain. Annual Review of Neuroscience 29: 387–415.

Catterall WA, Dib‐Hajj S, Meisler MH and Pietrobon D (2008) Inherited neuronal ion channelopathies: new windows on complex neurological diseases. Journal of Neuroscience 28 (46): 11768–11777.

Matthews E, Fialho D, Tan SV, et al. (2010) The non‐dystrophic myotonias: molecular pathogenesis, diagnosis and treatment. Brain 133 (Pt 1): 9–22.

Pietrobon D (2010) Ca(V)2.1 channelopathies. Pflügers Archiv 460 (2): 375–393.

Spillane J, Kullmann DM and Hanna MG (2016) Genetic neurological channelopathies: molecular genetics and clinical phenotypes. Journal of Neurology, Neurosurgery and Psychiatry 87: 37–48.

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Raja Rayan, Dipa L, and Hanna, Michael G(Jan 2018) Ion Channels and Human Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005166.pub3]