Pathophysiology of ion channel mutations

Current Opinion in Genetics and Development

Volumn 6, Issue 3, 1996, Pages 326-333

  Keating, Mark T ^a   Sanguinetti, Michael C ^b  

^a HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^b UNIVERSITY OF UTAH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ION CHANNEL;

GENE MUTATION; HEART ARRHYTHMIA; NERVE DEGENERATION; NERVOUS SYSTEM DEVELOPMENT; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW;

EID: 0030001098     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(96)80010-4     Document Type: Article

References (53)

1. Jiang C, Atkinson D, Towbin JA, Lehmann M, Splawski I, Li H, Taggart RT, Timothy K, Schwartz PJ, Vincent GM, Moss AJ, Keating MT: Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet 1994, 8:141-147.
2. Curran ME, Splawski I, Timothy K, Vincent GM, Green E, Keating MT: A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995, 80:795-803. This manuscript demonstrated that mutations in HERG, a putative potassium channel gene, cause an inherited cardiac arrhythmia, LOT. The discovery was the first to demonstrate that mutations in cardiac ion channel genes cause susceptibility to life-threatening arrhythmias.
3. Wang Q, Curran M, Splawski I, Burn T, Millholland J, VanRaay T, Shen J, Timothy K, Vincent GM, De Jager T et al.: Positional cloning of a novel cardiac channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996, 12:1-23. In this manuscript, positional cloning techniques were used to identify a novel cardiac potassium channel gene, KVLQT1, and demonstrate that mutations in this gene cause the most common form of inherited LOT syndrome. KVLQT1 is predicted to be a voltage-gated potassium channel important for myocellular repolarization. LQT-associated mutations were predicted to have a dominant negative effect on KVLQT1 function.
4. r channels provided a mechanistic link between inherited and acquired cardiac arrhythmias.
5. Trudeau M, Warmke J, Ganetzky B, Robertson G: HERG, a human inward rectifier in the voltage-gated potassium channel family. Science 1995, 269:92-95.
6. + channel. Circ Res 1996, 78:499-503.
7. + channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci USA 1996, 93:2208-2212. Here, we demonstrated that LQT-associated mutations in HERG cause loss, alteration and dominant-negative suppression of HERG function. Reduced repolarizing HERG potassium current presumably leads to increased myocellular excitability and arrhythmia susceptibility.
8. Browne D, Gancher S, Nutt J, Brunt E, Smith E, Kramer P, Litt M: Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet 1994, 8:136-140. This manuscript was the first to demonstrate that mutations in the human brain potassium channel gene, KCNA1, cause episodic ataxia and myokymia (muscle rippling).
9. Browne D, Brunt E, Griggs R, Nutt J, Gancher S, Smith S, Litt M: Identification of two new KCNA1 mutations in episodic ataxia/myokymia families. Hum Mol Genet 1995, 4:1671-1672.
10. Adelman J, Bond C, Pessia M, Maylie J: Episodic ataxia results from voltage-dependent potassium channels with altered functions. Neuron 1995, 15:1449-1454. This manuscript showed that mutations in the voltage-dependent delayed rectifier potassium channel gene, KCNA1, associated with episodic ataxia cause loss, alteration and dominant-negative suppression of channel function.
11. George A, Crackower M, Abdalla J, Hudson A, Ebers G: Molecular basis of Thomsen's disease (autosomal dominant myotonia congenita). Nat Genet 1993, 3:305-310.
12. 2. Steinmeyer K, Lorenz C, Pusch M, Koch M, Jentsch T: Multimeric structure of CLC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen). EMBO J 1994, 13:737-743.
13. Gronemeier M, Condie A, Prosser J, Steinmeyer K, Jentsch T, Jockusch H: Nonsense and missense mutations in the muscular chloride channel gene CLC-1 of myotonic mice. J Biol Chem 1994, 269:5963-5967.
14. Heine R, George A, Pika U, Deymeer F, Rudel R, Lehmann-Horn F: Proof of a non-functional muscle chloride channel in recessive myotonia congenita (Becker) by detection of a 4 base pair deletion. Hum Mol Genet 1994, 3:1123-1128.
15. Loreru C, Meyer-Kleine C, Steinmeyer K, Koch M, Jentsch T: Genomic organization of the human muscle chloride channel CIC-1 and analysis of novel mutations leading to Becker-type myotonia. Hum Mol Genet 1994, 3:941-946.
16. George A, Sloan-Brown K, Fenichel G, Milchell G, Spiegel R, Pascuzzi R: Nonsense and missense mutations of the muscle chloride channel gene in patients with myotonia congenita. Hum Mo! Genet 1994, 3:2071-2072.
17. Pusch M, Steinmeyer K, Koch M, Jentsch T: Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CLC-1 chloride channel. Neuron 1995, 15:1455-1463. This manuscript provides the first demonstration that mutations in the skeletal muscle chloride channel, CLC-1, cause a dramatic shift in the voltage sensitivity of expressed channels, leading to a loss of function. These mutant channels cannot contribute to repolarization of skeletal muscle action potential, leading to myotonia.
18. Wang Q, Shen J, Splawski I, Atkinson DL, Li Z, Robinson J, Moss A, Towbin J, Keating MT: SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome, Cell 1995, 80:805-811. This work was the first to demonstrate that mutations in the cardiac sodium channel gene SCN5A cause LQT syndrome. These findings suggested that the cellular mechanism of the disease results from altered channel inactivation properties and continued depolarizing sodium current late in the plateau phase of the cardiac action potential.
19. Wang Q, Shen J, Li Z, Timothy K, Vincent GM, Priori S, Schwartz P, Keating MT: Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. Hum Mol Genet 1995, 4:1603-1607.
20. Benneti P, Yazawa K, Makita N, George A: Molecular mechanism for an inherited cardiac arrhythmia. Nature 1995, 376:683-685. This manuscript was the first to demonstrate that LQT-associated mutations in the cardiac sodium channel gene cause destabilization of the channel's inactivation gate and late channel reopenings.
21. Hoffman E, Lehmann-Horn F, Rudel R: Overexcited or inactive: Ion channels in muscle disease. Cell 1995, 80:681-686.
22. Yang N, Zhou M, Ptacek L, Barchi R, Horn R, George F: Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro. Proc Natl Acad Sci USA 1994, 91:12785-12789.
23. Zhou J, Spier S, Beech J, Hoffman E: Pathophysiology of sodium channelopathies: correlation of normal/mutant mRNA ratios with clinical phenotype in dominantly inherited periodic paralysis. Hum Mol Genet 1994, 3:1599-1603.
24. Ptacek L, Tawil R, Griggs R. Engel A, Layzer R, Kwiecinski H, McManis P, Santiago L, Moore M, Fouad G et al.; Dihydropydrine receptor mutations cause hypokalemic periodic paralysis. Cell 1994, 77:863-368. This is the first demonstration that mutations in the skeletal muscle voltage gated calcium channel gene (also known as the dihydropydrine receptor gene) cause episodic weakness associated with low serum potassium levels - hypokalemic periodic paralysis.
25. Jurkat-Rott K, Lehmann-Horn F, Elbaz A, Heine R, Gregg R, Hogan K, Powers P, Lapie P, Vale-Santos J, Weissenbach J, Fontaine B: A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet 1994, 3:1415-1419. This manuscript established that mutations in the dihydropydrine receptor gene cause hypokalemic periodic paralysis.
26. Sipos I, Jurkatt-Rott K, Harasztosi Cs, Fontaine B, Kovacs L, Metzer W, Lehmann-Horn F: Skeletal muscle DHP receptor mutations alter calcium currents in human hypokalaemic periodic paralysis myotubes. J Physiol 1995, 483:299-306.
27. + channel Is made of three homologous subunits. Nature 1994, 367:463-467. This study defined the primary structure of the genes that encode the epithelial sodium channel, demonstrating that it comprises three homologous subunits that interact to form functional channels.
28. Snyder P, McDonald F, Stokes J, Welsh M: Membrane topology of the amiloride-sensitlve epithelial sodium channel. J Biol Chem 1994, 269:24379-24383.
29. Shimkets R, Warnock D, Bositis C, Nelson-Williams C, Hansson J, Schambelan M, Gill J, Ulick S, Milora R, Finding J et al.: Liddle's syndrome: heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel. Cell 1994, 79:407-414. Here, the authors demonstrate that mutations in the β subunit of the epithelial sodium channel cause Liddle syndrome (pseudo aldosteronism), an autosomal dominant form of human hypertension. The data presented suggest that the mechanism of Liddle syndrome is constitutive activation of an amiloride-sensitive distal nephronal epithelial sodium channel. These mutations lead to increased sodium resorption by the kidney and susceptibility to hypertension.
30. Hansson J, Nelson-Will Jams C, Suzuki H, Schild L, Shimkets R, Lu Y, Canessa C, Iwasaki T, Rossier B, Lifton R: Hypertension caused by a truncated epithelial sodium channel γ subunit: genetic heterogeneity of Liddle syndrome. Nat Genet 1995, 11:76-82. This manuscript showed that mutations in the γ subunit of the epithelial sodium channel cause susceptibility to hypertension in Liddle syndrome.
31. Schild L, Caness C, Shimkets R, Gaulschi I, Lifton R, Rossier B; A mutation in the epithelial sodium channel causing Liddle disease Increases channel activity in the Xenopus faevis oocyte expression system. Proc Natl Acad Sci USA 1995, 92:5699-5703. In this manuscript, the authors expressed Liddle syndrome associated mutant β subunits of the epithelial sodium channel with wild-type α and γ sub-units in Xenopus oocytes, demonstrating an increase in the macroscopic amiloride-sensitive sodium current.
32. + channel. Cell 1995, 83:969-978. This is the first demonstration that Liddle syndrome associated mutations in the epithelial sodium channel genes cause an increase in the number of sodium channels in the apical membrane and do not alter single-channel conductance or open-state probability.
33. Jung J, Preston G, Smith B, Guggino W, Agre P: Molecular structure of the water channel through aquaporin CHIP. J Biol Chem 1994, 269:14648-14654.
34. Deen P, Verdijk M, Knoers N, Wieringa B, Monnens L, Van Os C, Van Oost B: Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 1994, 264:92-95. This was the first demonstration that the aquaporin-2 water channel was required for concentration of urine by the kidney. These findings suggested that mutations in the aquaporin-2 water channel gene might cause diabetes insipidus. Support for this hypothesis was demonstrated in one patient.
35. Van Lieburg A, Verdijk M, Knoers V, Van Essen A, Poresmans W, Mallmann R, Monnens L, Van Oost B, Van Os C, Deen P: Patients with autosomal nephrogenic diabetes insipidus nomozygous for mutations in the aquaporin 2 water-channel gene. Am J Hum Genet 1994, 55:648-652. This manuscript identified missense mutations and a single nucleotide deletion in the aquaporin 2 gene in three individuals with nephrogenic diabetes insipidus. Expression of the mutants in Xenopus oocytes showed that the resultant channels were nonfunctional. These data indicate that mutations in the aquaporin-2 water channel gene can cause autosomal recessive nephrogenic diabetes insipidus.
36. Deen P, Croes H, Van Aubel R, Ginsel L, Van Os C: Water channels encoded by mutant aquaporin-2 genes in nephrogenic diabetes insipidus are impaired in their cellular routing. J Clin Invest 1995, 95:2291-2296. This study presented immunolocalization data suggesting that disease-associated mutant forms of the aquaporin-2 water channel proteins fail to reach the plasma membrane, leading to nonfunctional water channels.
37. Preston G, Smith B, Zeidel M, Moulds J, Agre P: Mutations in aquaporin-1 in phenotypically normal humans without functional CHIP water channels. Science 1994, 265:1585-1587.
38. Gunderson K, Kopito R: Conformational states of CFTR associated with channel gating: the role of ATP binding and hydrolysis. Cell 1995, 62:231-239. In this manuscript, electrophysiologic analyses of wild-type and mutant CFTR channels indicated that binding of ATP causes a reversible transition from the closed to an open state. Transition from this open state requires ATP hydrolysis.
39. Schwiebert E, Egan M, Hwang T, Fulmer S, Allen S, Cutting G, Guggino W: CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP. Cell 1995, 81:1063-1073. Physiological studies have suggested that CFTR can interact to modulate outwardly rectifying chloride channels in addition to being a chloride channel itself. Data provided in this manuscript indicated that CFTR regulates outwardly rectifying chloride channels by triggering the transport and release of ATP. ATP, in turn, activates non-CFTR chloride channels.
40. Reisin I, Prat A, Abraham E, Amara J, Gregory R, Ausiello D, Cantiello H: The cystic fibrosis transmembrane conductance regulator is a dual ATP and chloride channel. J Biol Chem 1994, 269:20584-20591.
41. Jensen T, Loo M, Pind S, Williams D, Goldberg A, Riordan J: Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 1995, 83:129-135. CFTR levels are tightly regulated, in part by protein degradation. Proper trafficking in early degradation of mutant CFTR proteins is thought to be mechanistically important in cystic fibrosis. This manuscript demonstrated that the molecular mechanisms of CFTR processing include degradation in the proteasome.
42. Ward C, Omura S, Kopito R: Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 1995, 83:121-127 This manuscript demonstrated that the ubiquitin-proteasome pathway is im-portant for CFTR degradation.
43. Sine S, Ohno K, Bouzat C, Auerbach A, Milone M, Pruitt J, Engel A: Mutation of the acetylcholine receptor a subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron 1995, 15:229-239. This study demonstrated that mutations in the AChR a subunit cause slow-channel myasthenic syndrome in several individuals. Electrophysiological analysis revealed a decreased rate of acetylcholine disassociation, causing the mutant receptors to open repeatedly during ligand occupancy, thereby altering the synaptic response.
44. Ohno K, Hutchinson D, Milone M, Brengman J, Bouzat C, Sine S, Engel A: Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the ε subunit. Proc Natl Acad Sci USA 1995, 92:758-762.
45. Gomez C, Gammack J: A leucine-to-phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow-channel syndrome. Neurology 1995, 45:982-985.
46. Steinlein O, Mulley J, Propping P, Wallace R, Phillips H, Sutherland G, Scheffer I, Berkovic S: A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995, 11:201-203. This study presented data suggesting that a missense mutation in the neuronal nicotinic AChR may be the cause of autosomal dominant nocturnal frontal lobe epilepsy in humans. The functional consequences of this mutant are not yet known.
47. 1 subunit of the Inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nat Genet 1993, 5:351-358.
48. Rajendra S, Lynch J, Pierce K, French C, Barry P, Schofield P: Startle disease mutations reduce the agonist sensitivity of the human inhibitory glycine receptor. J Biol Chem 1994, 269:18739-18742. This manuscript demonstrated that mutations in the glycine receptor, a ligand-gated chloride channel associated with Startle disease, disrupt receptor function by causing a dramatic decrease in sensitivity to glycine. Startle disease mutations in the glycine receptor reduce the efficiency of glycinergic inhibitory neurotransmission.
49. Patil N, Cox D, Bhat D, Faham M, Myers R, Peterson A: A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation. Nat Genet 1995, 11:126-129. This manuscript demonstrated that a missense mutation in a G-protein-coupled inward rectifier potassium channel gene cause the weaver phenotype in mice. Homozygous animals suffer from severe ataxia that is thought to result from a block in neuronal differentiation in the cerebellum.
50. Huang M, Chalfie M: Gene interactions affecting mechanosensory transduction in Caenorhabditis elegans. Nature 1994, 367:467-470. This study characterizes two genes in C. elegans that are critical for mechanosensory transduction, and, from DNA sequence homology, are similar to the amiloride-sensitive sodium channel λ, βand γ subunits.
51. Treinin M, Chalfie M: A mutated acetylcholine receptor subunit causes neuronal degeneration in C. elegans. Neuron 1995, 14:871-877. This manuscript demonstrated that a gain-of-function mutation in an AChR subunit leads to degeneration of a set of neurons in C. elegans. Because antagonists of nicotinic AChRs suppress the mutant phenotype, these data suggest that channel hyperactivity may underlie neurodegeneration in this model.
52. Burgess D, Kohrman D, Galt J, Plummer N, Jones J, Spear B, Meisler M: Mutation of a new sodium channel gene, Scn8a, in the mouse mutant 'motor endplate disease'. Nat Genet 1995, 10:461-465. This manuscript demonstrated that mutation of a brain sodium channel gene is responsible for neurodegeneration in the mouse mutant known as 'motor endplate disease'.
53. Lloyd SE, Pearce SHS, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Brolino A, Devoto M, Goodyer P et al: A common molecular basis for three inherited kidney stone diseases. Nature 1996, 379:445-449.