Introduction

Abstract

“Ion Channelopathies: Hereditary Dysfunction of Ion Channels” was the theme of a jointly organized International Society of Nephrology Forefronts in Nephrology and American Society of Nephrology Basic Science Conference held at the Skytop Lodge amid the breathtaking autumn scenery of the Pocono Mountains in western Pennsylvania. The conference was an opportunity to gather many prominent scientists from around the world for the sole purpose of discussing the role of ion channel gene mutations in inherited disease processes. In fact, this was the largest meeting ever held that was dedicated solely to ion channel disease syndromes, and perhaps we can look forward to other similar meetings in the future. The conference was originally conceived by Steve Hebert and was developed in conjunction with Bill Guggino and Bruce Stanton. Ion channels are integral membrane proteins that mediate the rapid and selective movement of charged inorganic solutes and water across cell membranes. After more than 50 years of investigation, it is widely appreciated that ion channels are vital to most cellular and physiological functions in virtually all living organisms. Ion channels participate in secretion and reabsorption in epithelial tissues, membrane excitability in nerve, muscle and cardiac cells, signal transduction and endocrine gland function, and the control of cell volume. In addition to these diverse and critical physiological functions, ion channels are also well known targets for a variety of pharmacological agents, such as anti-arrhythmics/local anesthetics, anticonvulsants, antihypertensives, diuretics, antidiabetic drugs, and anti-anginal agents. Before 1989, the concept of a genetic defect in an ion channel gene was speculative. Research during the past 10 years has revealed a startling wealth and diversity of genetic syndromes caused by mutations in genes encoding ion channel proteins. Now more than 30 human genetic diseases have been identified in association with mutations in more than 25 different ion channel-encoding genes Table 1. In fact, most of these discoveries have been made since 1991, and the only current speculation is how many more disorders affecting other ion channel genes will be identified in the future. There have been many surprises along the way: chloride channels in X-linked nephrolithiasis, calcium channels in hypokalemic periodic paralysis, potassium channels in Bartter's syndrome, and others.Table 1Time line of ion channel disease discoveries1989Cystic fibrosis (CFTR)1.Riordan J.R. Rommens J.M. Kerem B. Alon N. Rozmahel R. Grzelczak Z. Zielenski J. Lok S. Plavsic N. Chou J.L. Drumm M.L. Iannuzzi M.C. Collins F.S. Tsui L.C. Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA.Science. 1989; 245: 1066-1072Crossref PubMed Scopus (5602) Google Scholar,2.Rommens J.M. Iannuzzi M.C. Kerem B. Drumm M.L. Melmer G. Dean M. Rozmahel R. Cole J.L. Kennedy D. Hidaka N. Zsiga M. Buchwald M. Riordan J.R. Tsui L.C. Collins F.S. Identification of the cystic fibrosis gene: Chromosome walking and jumping.Science. 1989; 245: 1059-1065Crossref PubMed Scopus (2401) Google Scholar1991Malignant hyperthermia susceptibility (muscle Ca release channel, RYR1)3.Fujii J. Otsu K. De Zorzato F. Leon S. Khanna V.K. Weiler J.E. O'brien P.J. MacLennan D.H. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia.Science. 1991; 253: 448-451Crossref PubMed Scopus (1200) Google ScholarHyperkalemic periodic paralysis (muscle Na channel, SCN4A)4.Ptacek L.J. George A.L. Griggs R.C. Tawil R. Kallen R.G. Barchi R.L. Robertson M. Leppert M.F. Identification of a mutation in the gene causing hyperkalemic periodic paralysis.Cell. 1991; 67: 1021-1027Abstract Full Text PDF PubMed Scopus (326) Google Scholar,5.Rojas C.V. Wang J. Schwartz L.S. Hoffman E.P. Powell B.R. Brown R.H. A Met-to-Val mutation in the skeletal muscle Na+ channel α-subunit in hyperkalemic periodic paralysis.Nature. 1991; 354: 387-389Crossref PubMed Scopus (278) Google Scholar1992Paramyotonia congenita (muscle Na channel, SCN4A)6.McClatchey A.I. Van Den Bergh P. Pericak-Vance M.A. Raskind W. Verellen C. McKenna-Yasek D. Keshav R. Haines J.L. Bird T. Brown R.H. Gusella J.F. Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita.Cell. 1992; 68: 769-774Abstract Full Text PDF PubMed Scopus (197) Google Scholar,7.Ptacek L.J. George A.L. Barchi R.L. Griggs R.C. Riggs J.E. Robertson M. Leppert M.F. Mutations in an S4 segment of the adult skeletal muscle sodium channel gene cause paramyotonia congenita.Neuron. 1992; 8: 891-897Abstract Full Text PDF PubMed Scopus (212) Google ScholarRecessive generalized myotonia (muscle Cl channel, CLCN1)8.Koch M.C. Steinmeyer K. Lorenz C. Ricker K. Wolf F. Otto M. Zoll B. Lehmann-Horn F. Grzeschik K.H. Jentsch T.J. The skeletal muscle chloride channel in dominant and recessive human myotonia.Science. 1992; 257: 797-800Crossref PubMed Scopus (598) Google Scholar1993Autosomal dominant myotonia congenita—Thomsen's disease (muscle Cl channel, CLCN1)9.George A.L. Crackower M.A. Abdalla J.A. Hudson A.J. Ebers G.C. Molecular basis of Thomsen's disease (autosomal dominant myotonia congenita).Nat Genet. 1993; 3: 305-310Crossref PubMed Scopus (235) Google ScholarCentral core disease (muscle Ca release channel, RYR1)10.Zhang Y. Chen H.S. De Khanna V.K. Leon S. Phillips M.S. Schappert K. Britt B.A. Brownell A.K.W. MacLennan D.H. A mutation in the human ryanodine receptor gene associated with central core disease.Nat Genet. 1993; 5: 46-50Crossref PubMed Scopus (279) Google Scholar,11.Quane K.A. Healy J.M.S. Keating K.E. Manning B.M. Couch F.J. Palmucci L.M. Doriguzzi C. Fagerlund T.H. Berg K. Ording H. Bendixen D. Mortier W. Linz U. Muller C.R. McCarthy T.V. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia.Nat Genet. 1993; 5: 51-55Crossref PubMed Scopus (294) Google ScholarHyperekplexia (glycine receptor, GLRA1)12.Shiang R. Ryan S.G. Zhu Y.Z. Hahn A.F. O'connell P. Wasmuth J.J. Mutations in the α1 of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia.Nat Genet. 1993; 5: 351-358Crossref PubMed Scopus (417) Google Scholar1994Liddle's syndrome (epithelial Na channel, SCNN1B, SCNN1G)13.Shimkets R.A. Warnock D.G. Bositis C.M. Nelson-Williams C. Hansson J.H. Schambelan M. Gill J.R. Ulick S. Milora R.V. Findling J.W. Canessa C.M. Rossier B.C. Lifton R.P. Liddle's syndrome: Heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel.Cell. 1994; 79: 407-414Abstract Full Text PDF PubMed Scopus (1141) Google ScholarAutosomal recessive nephrogenic diabetes insipidus (renal water channel, AQP2)14.Deen P.M.T. Verdijk M.A.J. Knoers N.V.A.M. Wieringa B. Monnens L.A.H. Van Os C.H. Van Oost B.A. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine.Science. 1994; 264: 92-95Crossref PubMed Scopus (718) Google ScholarDent's disease (X-linked nephrolithiasis; renal Cl channel, CLCN5)15.Fisher S.E. Black G.C.M. Lloyd S.E. Hatchwell E. Wrong O. Thakker R.V. Craig I.W. Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis).Hum Mol Genet. 1994; 3: 2053-2059PubMed Google Scholar,16.Lloyd S.E. Pearce S.H.S. Fisher S.E. Steinmeyer K. Schwappach B. Scheinman S.J. Harding B. Alessandra B. Devota M. Goodyear P. Rigden S.P.A. Wrong O. Jentsch T.J. Craig I.W. Thakker R.V. A common molecular basis for three inherited kidney stone diseases.Nature. 1996; 379: 445-449Crossref PubMed Scopus (586) Google ScholarEpisodic ataxia with myokymia (K channel, KCN4A)17.Browne D.L. Gancher S.T. Nutt J.G. Brunt E.R.P. Smith E.A. Kramer P. Litt M. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1.Nat Genet. 1994; 8: 136-140Crossref PubMed Scopus (646) Google ScholarHypokalemic periodic paralysis (muscle Ca channel, CACNLA3)18.Ptacek L.J. Tawil R. Griggs R.C. Engel A.G. Layzer R.B. Kwiecinski H. McManis P.G. Santiago L. Moore M. Fouad G. Bradley P. Leppert M.F. Dihydropyridine receptor mutations cause hypokalemic periodic paralysis.Cell. 1994; 77: 863-868Abstract Full Text PDF PubMed Scopus (360) Google Scholar1995Familial persistent hyperinsulinemia (pancreatic KATP channel/sulfonylurea receptor, SUR1)19.Thomas P.M. Cote G.J. Wohllk N. Haddad B. Mathew P.M. Rable W. Aquilar-Bryan L. Gagel R.F. Bryan J. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy.Science. 1995; 268: 426-429Crossref PubMed Scopus (714) Google ScholarCongenital long QT syndrome—LQT2 (cardiac K channel, HERG)20.Curran M.E. Splawski I. Timothy K.W. Vincent G.M. Green E.D. Keating M.T. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.Cell. 1995; 80: 795-803Abstract Full Text PDF PubMed Scopus (1917) Google ScholarCongenital long QT syndrome—LQT3 (cardiac Na channel, SCN5A)21.Wang Q. Shen J. Splawski I. Atkinson D. Li Z. Robinson J.L. Moss A.J. Towbin J.A. Keating M.T. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.Cell. 1995; 80: 805-811Abstract Full Text PDF PubMed Scopus (1387) Google ScholarAutosomal recessive retinitis pigmentosa (cGMP-gated channel, CNCG1)22.Dryja T.P. Finn J.T. Peng Y.W. McGee T.L. Berson E.L. Yau K.W. Mutations in the gene encoding the α subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.Proc Natl Acad Sci USA. 1995; 92: 10177-10181Crossref PubMed Scopus (233) Google ScholarSlow-channel myasthenic syndrome (muscle acetylcholine receptor, CHRNB1, CHRNE)23.Gomez C.M. Gammack J.T. A leucine-to-phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow-channel syndrome.Neurology. 1995; 45: 982-985Crossref PubMed Scopus (51) Google Scholar,24.Engel A.G. Ohno K. Milone M. Wang H.L. Nakano S. Bouzat C. Pruitt J.N. Hutchinson D.O. Brengman J.M. Bren N. Sieb J.P. Sine S.M. New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome.Hum Mol Genet. 1996; 5: 1217-1227Crossref PubMed Scopus (173) Google ScholarNocturnal frontal lobe epilepsy (neuronal acetylcholine receptor, CHRNA4)25.Steinlein O.K. Mulley J.C. Propping P. Wallace R.H. Phillips H.A. Sutherland G.R. Scheffer I.E. Berkovic S.F. A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.Nat Genet. 1995; 11: 201-203Crossref PubMed Scopus (939) Google Scholar1996Bartter's syndrome (renal K channel, ROMK)26.Simon D.B. Karet F.E. Rodriguez-Soriano J. Hamdan J.H. Dipietro A. Trachtman H. Sanjad S.A. Lifton R.P. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK.Nat Genet. 1996; 14: 152-156Crossref PubMed Scopus (677) Google ScholarCongenital long QT syndrome—LQT1 (cardiac K channel, KvLQT1)27.Wang Q. Curran M.E. Splawski I. Burn T.C. Millholland J.M. Vanraay T.J. Shen J. Timothy K.W. Vincent G.M. De Jager T. Schwartz P.J. Towbin J.A. Moss A.J. Atkinson D.L. Landes G.M. Connors T.D. Keating M.T. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.Nat Genet. 1996; 12: 17-23Crossref PubMed Scopus (1436) Google ScholarPseudohypoaldosteronism (epithelial Na channel, SCNN1A, SCNN1B, SCNN1G)28.Chang S.S. Grunder S. Hanukoglu A. Rosler A. Mathew P.M. Hanukoglu I. Schild L. Lu Y. Shimkets R. Nelson-Williams C. Rossier B.C. Lifton R.P. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalemic acidosis, pseudohypoaldosteronism type 1.Nat Genet. 1996; 12: 248-253Crossref PubMed Scopus (661) Google ScholarFamilial persistent hyperinsulinemia (pancreatic inward rectifier K channel, KCNJ11)29.Thomas P. Ye Y. Lightner E. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy.Hum Mol Genet. 1996; 5: 1809-1812Crossref PubMed Scopus (365) Google ScholarMalignant hyperthermia susceptibility (muscle Ca channel, CACLN1A3)30.Monnier N. Procaccio V. Stieglitz P. Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the α1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle.Am J Hum Genet. 1997; 60: 1316-1325Abstract Full Text PDF PubMed Scopus (342) Google ScholarFamilial hemiplegic migraine (Ca channel, CACNL1A4)31.Ophoff R.A. Terwindt G.M. Vergouwe M.N. Van Eijk R. Oefner P.J. Hoffman S.M.G. Lamerdin J.E. Mohrenweiser H.W. Bulman D.E. Ferrari M. Haan J. Lindhout D. Van Ommen G.J.B. Hofker M.H. Ferrari M.D. Frants R.R. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.Cell. 1996; 87: 543-552Abstract Full Text Full Text PDF PubMed Scopus (2028) Google ScholarEpisodic ataxia type 2 (Ca channel, CACNL1A4)32.Jodice C. Mantuano E. Veneziano L. Trettel F. Sabbadini G. Calandriello L. Francia A. Spadaro M. Pierelli F. Salvi F. Ophoff R.A. Frants R.R. Frontali M. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p.Hum Mol Genet. 1997; 6: 1973-1978Crossref PubMed Scopus (243) Google Scholar1997Bartter's syndrome (renal Cl channel, CLCNKB)33.Simon D.B. Bindra R.S. Mansfield T.A. Nelson-Williams C. Mendonca E. Stone R. Schurman S. Nayir A. Alpay H. Bakkaloglu A. Rodriguez-Soriano J. Morales J.M. Sanjad S.A. Taylor C.M. Pilz D. Brem A. Trachtman H. Griswold W. Richard G.A. John E. Lifton R.P. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III.Nat Genet. 1997; 17: 171-178Crossref PubMed Scopus (712) Google ScholarCongenital long QT syndrome—LQT5 (cardiac K channel subunit, KCNE1)34.Splawski I. Tristani-Firouzi M. Lehmann M.H. Sanguinetti M.C. Keating M.T. Mutations in the hminK gene cause long QT syndrome and suppress IKs function.Nat Genet. 1997; 17: 338-340Crossref PubMed Scopus (651) Google ScholarAutosomal dominant spinocerebellar ataxia type 6 (Ca channel, CACNL1A4)35.Zhuchenko O. Bailey J. Bonnen P. Ashizawa T. Stockton D.W. Amos C. Dobyns W.B. Subramony S.H. Zoghbi H.Y. Lee C.C. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A voltage-dependent calcium channel.Nat Genet. 1997; 15: 62-69Crossref PubMed Scopus (1371) Google ScholarJervell and Lange–Nielsen cardioauditory syndrome (K channel, KvLQT1)36.Neyroud N. Tesson F. Denjoy I. Leibovici M. Donger C. Barhanin J. Fauré S. Gary F. Coumel P. Petit C. Schwartz K. Guicheney P. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.Nat Genet. 1997; 15: 186-189Crossref PubMed Scopus (716) Google Scholar1998Benign familial neonatal convulsions (K channel, KCNQ2)37.Singh N.A. Charlier C. Stauffer D. Dupont B.R. Leach R.J. Melis R. Ronen G.M. Bjerre I. Quattlebaum T. Murphy J.V. McHarg M.L. Gagnon D. Rosales T.O. Peiffer A. Anderson V.E. Leppert M. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.Nat Genet. 1998; 18: 25-29Crossref PubMed Scopus (981) Google ScholarBenign familial neonatal convulsions (K channel, KCNQ3)38.Charlier C. Singh N.A. Ryan S.G. Lewis T.B. Reus B.E. Leach R.J. Leppert M. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family.Nat Genet. 1998; 18: 53-55Crossref PubMed Scopus (792) Google ScholarFamilial idiopathic ventricular fibrillation—Brugada syndrome (cardiac Na channel, SCN5A)39.Chen Q. Kirsch G.E. Zhang D. Brugada R. Brugada J. Brugada P. Potenza D. Moya A. Borggrefe M. Breithardt G. Ortiz-Lopez R. Wang Z. Antzelevitch C. O'brien R.E. Schulze-Bahr E. Keating M.T. Towbin J.A. Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.Nature. 1998; 392: 293-296Crossref PubMed Scopus (1479) Google ScholarGeneralized epilepsy with febrile seizures plus (Na channel 1β subunitSCN1B)40.Wallace R.H. Wang D.W. Singh R. Scheffer I.E. George Jr, Al Phillips H.A. Saar K. Reis A. Johnson E.W. Sutherland G.R. Berkovic S.F. Mulley J.C. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel β1 subunit gene SCN1B.Nat Genet. 1998; 19: 366-370Crossref PubMed Scopus (92) Google ScholarTotal color blindness (cGMP-gated cation channel, CNGA3)41.Kohl S. Marx T. Giddings I. Jagle H. Jacobson S.G. Apfelstedt-Sylia E. Zrenner E. Sharpe L.T. Wissinger B. Total colour blindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel.Nat Genet. 1998; 19: 257-259Crossref PubMed Scopus (266) Google ScholarX-linked congenital stationary night blindness (Ca channel, CACNA1F)42.Bech-Hansen N.T. Naylor M.J. Maybaum T.A. Pearce W.G. Koop B. Fishman G.A. Mets M. Musarella M.A. Boycott K.M. Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness.Nat Genet. 1998; 19: 264-267Crossref PubMed Scopus (401) Google Scholar,43.Strom T.M. Nyakatura G. Apfelstedt-Sylla E. Hellebrand H. Lorenz B. Weber B.H.F. Wutz K. Gutwillinger N. Rüther K. Drescher B. Sauer C. Zrenner E. Meitinger T. Rosenthal A. Meindl A. An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness.Nat Genet. 1998; 19: 260-263Crossref PubMed Scopus (373) Google Scholar1999Sporadic long QT syndrome (K channel subunit, KCNE2)44.Abbott G.W. Sesti F. Splawski I. Buck M.E. Lehmann M.H. Timothy K.W. Keating M.T. Goldstein S.A. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.Cell. 1999; 97: 175-187Abstract Full Text Full Text PDF PubMed Scopus (1138) Google ScholarAutosomal dominant nonsyndromic deafness—DFNA2 (K channel, KCNQ4)45.Kubisch C. Schroeder B.C. Friedrich T. Lutjohann B. El-Amraoui A. Marlin S. Petit C. Jentsch T.J. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness.Cell. 1999; 96: 437-446Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar Open table in a new tab Studies of diseases caused by genetic defects in ion channels have brought forth new information along two scientific frontiers. As with the discovery of any genetic defect, work in the ion channel disease field has made significant contributions to revealing the fundamental molecular pathogenesis of disorders involving a wide variety of disease processes. Included in these accomplishments have been the recognition of the molecular basis for certain forms of familial hypertension, syndromes of inherited renal salt and water wasting, nephrolithiasis, a variety of inherited muscle diseases, sudden cardiac death, deafness, familial ataxias, and epilepsy. Defining the molecular pathogenesis of a disease is a critical step toward developing new diagnostic and therapeutic strategies. The second scientific area that ion channel disease research has contributed has been in the elucidation of the fundamental biology of ion channel proteins. Because many genetic mutations affect critical ion channel functions, many researchers have been able to discern important relationships between function and structure. These advances have contributed to our basic understanding of how ion channels work, and this will ultimately contribute greatly to the development of pharmacologic agents that target these molecules. Studies of ion channel disorders have helped quench a seemingly insatiable appetite for understanding the basic functional biology of ion channel proteins, including structure–function relationships, modulation by accessory subunits, and appreciation of their cellular biology. In view of the great potential for discovery of new ion channels and ion channel diseases, there has been strong interest among a variety of biomedical scientists to examine this field in depth. In particular, the opportunities to advance our understanding of disorders affecting renal fluid and electrolyte transport, including hypertension, provided the incentive for the International Society of Nephrology in conjunction with the American Society of Nephrology to jointly sponsor this conference. The intent of the conference was to stimulate new ideas that would ultimately lead to greater advances in ion channel disease biology, as well as improved diagnostic and therapeutic modalities. An eclectic mix of scientists was assembled to provide opportunities for cross-fertilization of ideas and expertise. The conference served to disseminate information about ion channel disease research and provided a forum for sharing the latest experimental approaches to studying these fascinating syndromes. The conference was organized into six main sessions, two poster sessions, and three state-of-the-art lectures. The organizational structure focused on common mechanisms of ion channel dysfunction to facilitate the goals of the conference. By all accounts, this plan was a tremendous success. The following paragraphs briefly summarize the content of the conference, and several more formal excerpts have been generously supplied by many of the participants to form this Symposium issue of Kidney International. The identification and functional characterization of ion channel mutations have, in many cases, revealed important relationships between structure and function. This session highlighted several examples of this area of investigation. The goal of this session was to correlate not only structure with function, but also phenotype with molecular and biophysical characteristics of ion channel dysfunction. Following a brief overview of ion channel structure and function given by Richard Horn (Jefferson Medical College), Stephen Cannon (Massachusetts General Hospital, Harvard Medical School) reviewed the spectrum of sodium channel gating disturbances in the nondystrophic myotonias and periodic paralysis. These primary muscle disorders illustrate some of the earliest defined and most extensively characterized ion channel diseases. The subsequent presentations focused attention on disorders caused by disturbances in ion channel gating or permeation properties. Christopher Gomez (University of Minnesota) presented his work on mutant nicotinic acetylcholine receptors as causes of the slow channel myasthenic syndromes. Bernard Rossier (University of Lausanne, Switzerland) discussed gain and loss of function in the epithelial sodium channel in Liddle's syndrome and familial pseudohypoaldosteronism, respectively. The final presentation of the session focused on ion permeation defects in mutant chloride channels (Christoph Fahlke, Vanderbilt University) and how this led to revealing important structural determinants of ion selectivity in the ClC family of chloride channels. This session addressed the biology of accessory subunits and their role in the pathogenesis of ion channel diseases. In the opening presentation, Lydia Aguilar-Bryan (Baylor College of Medicine) described her work on the sulfonylurea receptor (SUR) and inward rectifier, KIR6.2, the two main components of the pancreatic ATP-sensitive potassium channel and the molecular genetic basis for familial hyperinsulinemic hypoglycemia. Jacques Barhanin (CRNS, France) discussed the role of another accessory subunit important for potassium channel function, minK, which has been linked to congenital long QT syndrome and congenital deafness. Calcium channels are important regulators of muscle, cardiac, and neuroneal excitability, and there are several types and isoforms of accessory subunits. Miriam Misler (University of Michigan) described her work identifying calcium channel accessory subunits as causes of central nervous system disorders. Structural mutations in ion channel proteins may not always cause disease by directly interfering with function of the channel at the cell membrane. Several examples are known in which a molecular defect restricts or impedes the ability of the ion channel protein to assemble or traffic in the cell. After an overview of protein trafficking by Dennis Brown (Massachusetts General Hospital, Harvard Medical School, MA, USA), William Skach (University of Pennsylvania, PA, USA) discussed defects in processing and trafficking of the cystic fibrosis gene, CFTR. Next, Carel Van Os (University of Nijmegen, The Netherlands) described how defects in the post-translational processing of water channels cause the autosomal form of nephrogenic diabetes insipidus. The third lecture given jointly by Daniella Rotin (University of Toronto) and Olivier Staub (University of Lausanne) explained how defining the Liddle's disease defect revealed an important interplay between the epithelial sodium channel and Nedd4, a cytosolic protein–protein interaction critical for channel regulation. Because of the clear importance of understanding defects in protein trafficking, the last two lectures in this session expounded on more general biological themes relating to ion channel assembly and targeting. Dennis Ausiello (Massachusetts General Hospital, Harvard Medical School) described his work on the interactions between ion channels and the cytoskeleton, whereas Michael Kaplan (Yale University) presented his research on the importance of PDZ domains in potassium channel targeting. Some ion channel disorders present a complex and multisystem phenotype that is not readily explained by understanding the abnormal functional attributes of the involved channel protein. Steve Hebert (Vanderbilt University) provided an overview of this area, and then Rajesh Thakker (Royal Post Graduate Medical School, London, England) and Thomas Jentsch (University of Hamburg, Germany) discussed the pathogenesis of Dent's disease and the biology of the CLC-5 chloride channel. The role of renal potassium and chloride channels in complex disease pathogenesis was presented by David Simon (Yale University), who related the common phenotypic expression of defects in multiple ion channels present in the thick ascending limb of the loop of Henle to the clinical entity, Bartter's syndrome. Finally, Kurt Beam (University of Colorado) discussed the spectrum of the calcium channel diseases, including his important work understanding disorders of excitation contraction coupling to illustrate how ion permeation is not the only important function of ion channels. In additional to understanding the pathophysiologic basis for ion channel diseases, an important aspect of this conference was a focus on the future development of novel therapeutic strategies specifically targeted to mutant ion channels. This session highlighted examples of new pharmacological and genetic approaches to such therapy. Kim Lawson (Sheffield Hallam University, England) presented an entertaining overview of an exciting new class of drugs, potassium channel openers, as potential therapeutic weapons in ion channel diseases caused by potassium channel mutations. In the next presentation, Pamela Zeitlin (Johns Hopkins University) discussed pharmacologic strategies for restoring CFTR-mediated chloride transport by employing chemical chaperones. Richard Boucher (University of North Carolina) provided an elegant overview of genetic approaches to treatment of genetic disease using cystic fibrosis as an illustration. Finally, Eduardo Marban (Johns Hopkins University) presented a novel strategy for modifying cardiac and neuroneal excitability by the introduction of ion channels into the heart and neurons with targeted viral vectors. Attendees and speakers who participated in “Ion Channelopathies: Hereditary Dysfunction of Ion Channels” synergized to make an outstanding forum for discussing this fascinating topic. In the future, as the fruits of the Human Genome Project are brought forth, we can expect additional discoveries in the area of ion channel genetics. Participants of this landmark conference strongly suggested planning for another such forum, possibly a Gordon Conference, to continue highlighting and disseminating important work in this area. We are all grateful to the International and American Societies of Nephrology for their foresight in promoting this scientific theme on the threshold of the new millennium. This conference was primarily supported by the International Society of Nephrology, the American Society of Nephrology, and the National Institutes of Health (DK54726), with additional support from the Muscular Dystrophy Association and Roche Laboratories.