mutations in kir2.1andersensyndrome

Cell, Vol. 105, 511–519, May 18, 2001, Copyright 2001 by Cell Press Mutations in Kir2.1 Cause the Developmental and Episodic Electrical Phenotypes of Andersen’s Syndrome Summary Andersen’s syndrome is characterized by periodic pa- ralysi s, cardi ac arrhy thmia s, and dysmorphic feat ures. We hav e map ped an And ersen’ s loc us to chromosome Nikki M. Plaster, 1 Rabi Tawil, 5 Martin Tristani-Firouzi, 4 Sonia Canu ´ n, 6 Saı ¨ d Bendahhou, 1 Akiko Tsunoda, 1 Matthew R. Donaldson, 1 Susan T. Iannaccone, 7 Ewout Brunt, 8 Richard Barohn, 9 John Clark, 10 Feza Deymeer, 11 Alfred L. George, Jr., 12 17q23 (maximum LOD 3.23 at 0) near the inward recti fying potas siumchannel gene KCNJ2. A missense Frank A. Fish, 12 Angelika Hahn, 13 Alexandru Nitu, 14 Coskun Ozdemir, 11 Piraye Serdaroglu, 11 mutation in KCNJ2 (encoding D71V) was identified in the linke d fami ly. Eightadditiona l mutat ions were iden - S.H. Subramony, 15 Gil Wolfe, 16 Ying-Hui Fu, 3 and Louis J. Pta ´ c ˇ ek 1,2,17 tified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of func- 1 Department of Human Genetics 2 Howard Hughes Medical Institute and Department tion and a domi nant nega tive effe ct in Kir2.1 curre nt as assaye d by vol tag e-c lamp. We con clu de tha t muta- of Neurology 3 Department of Neurobiology and Anatomy tions in Kir2.1 cau se And ersen’ s syndrome. The se findings suggest that Kir2.1 plays an important role in 4 Department of Pediatrics University of Utah devel opme ntal signa ling in addit ion to its previo usly recognized function in controlling cell excitability in Salt Lake City, Utah 84112 5 Neuromuscu lar Pathology skeletal muscle and heart. University of Rochester School of Medicine Rochester, New York 14642 Introduction 6 Department de Genetica Hospital General Dr. Manuel Gea Gonza ´ lez Andersen’s syndrome (AS) is a rare disorder character- Calzada de Tlalpan 4800 ized by peri odic para lysis , cardiac arrhy thmias, and Mexico D.F. 14000 dysmorphic features (Figure 1) (Canun et al., 1999; San- 7 Department of Neurology sone et al., 1997; Tawil et al., 1994). The dysmorphology Texas Scottish Rite Hospital includes short stature, scoliosis (curvature of the spine), Dallas, Texas 75219 clinodactyly (permanent lateral or medial curve of a fin- 8 Kliniek voor Neurologie ger or toe ), hyp ert elorism (wi de- seteyes) , small or pro m- Academish Ziekenhuis Groningen ine nt ears tha t arelow setor sla nte d, mi crogna thi a (small 9700 RB Groningen chin ), and broad fore head. AS occu rs eithe r spora dica lly Netherlands or asanautosomal dominant tra it.In ASfami lie s, exp res - 9 Department of Neurology sion of the char acte risti c trai ts is high ly varia ble (Fig- University of Kansas Medical Center ure 2A). Thus, it is likely that the AS protein plays a com- Kansas City, Kansas 66160 plex role in deve lopment and cell exci tabi lity, havi ng 10 Children’s Hospital Medical Center some redundancy with other proteins. This disorder is Akron, Ohio 44308 the fir st to demons tra te a pre dic ted lin k bet ween muscl e 11 Noroloji Anabilim and cardiac electrical phenotypes and also to provide Istanbul University Tip Fak an exci ting link between elec trica l episodicanddevelop- Capa Istanbul mental phenotypes. Turkiye 34390 The periodic paralyses and nondystrophic myotonias 12 Vanderbilt University Medical Center are a gro up of muscl e disord ers cha rac ter ize d by abn or- Nashville, Tennessee 37232 mal muscle relaxation (myotonia). This myotonia results 13 Department of Clinical and Neurological Sciences from muscle hyperexc itability that sometim es transitio ns London Health Sciences Center to inexcitability resulting in episodic weakness. Ventric- London Ontario ular tach yarrh ythmias are ana logou s to myot onia of Canada N6A 4GA skeletal muscle in that hyperexcitabilit y leads to an ab- 14 Department of Neurology normal series of hear t cont ract ions that can lead to Indiana University death. Approximately 300,000 Americans die of cardiac Indianapolis, Indiana 46202 arrhythmias each year (Kannel et al., 1987; Willich et al., 15 Department of Neurology 1987 ). The elec troph ysiol ogic al features of such dis- University of Mississippi Medical Center eases suggest an underlying defect in membrane excit- Jackson, Mississippi 39216 abi lit y. Thefirst ion chann el mutations con tri but ing to an 16 Southwestern Medical Center episo dic disor der were char acte rizedless than a deca de University of Texas ago when mutations in SCN4A, which encodes a volt- Dallas, Texas 75390 age -ga tedsodiumchannel, wer e sho wn to cause hyp er- kalemic periodic paralysis (Ptacek et al., 1991; Rojas et al., 1991). This muscle disease formed the basis of the growing group now known as the channelopathies and led to predi ctio ns that card iac dysrh ythmias, epil epsie s, 17 Correspondence: [email protected]

mutations in kir2.1andersensyndrome

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