Although mutations in more than 90 genes are known to cause CMT, the underlying genetic cause of CMT remains unknown in more than 50% of affected individuals. The discovery of additional genes that harbor CMT2-causing mutations increasingly depends on sharing sequence data on a global level. In this way-by combining data from seven countries on four continents-we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na+,K+-ATPase, as a cause of autosomal-dominant CMT2. Seven missense changes were identified that segregated within individual pedigrees: c.143T>G (p.Leu48Arg), c.1775T>C (p.Ile592Thr), c.1789G>A (p.Ala597Thr), c.1801_1802delinsTT (p.Asp601Phe), c.1798C>G (p.Pro600Ala), c.1798C>A (p.Pro600Thr), and c.2432A>C (p.Asp811Ala). Immunostaining peripheral nerve axons localized ATP1A1 to the axolemma of myelinated sensory and motor axons and to Schmidt-Lanterman incisures of myelin sheaths. Two-electrode voltage clamp measurements on Xenopus oocytes demonstrated significant reduction in Na+ current activity in some, but not all, ouabain-insensitive ATP1A1 mutants, suggesting a loss-of-function defect of the Na+,K+ pump. Five mutants fall into a remarkably narrow motif within the helical linker region that couples the nucleotide-binding and phosphorylation domains. These findings identify a CMT pathway and a potential target for therapy development in degenerative diseases of peripheral nerve axons.

Centre for Medical Research University of Western Australia and Harry Perkins Institute of Medical Research Nedlands WA 6009 Australia

Department of Biological Science Kongju National University Gongju 32588 Korea

Department of Neurology 2 Faculty of Medicine Charles University Prague and University Hospital Motol Prague 150 06 Czech Republic

Department of Neurology Carver College of Medicine University of Iowa Iowa City IA 52242 USA

Department of Neurology Perelman School of Medicine at the University of Pennsylvania Philadelphia PA 19104 USA

Department of Neurology Samsung Medical Center Sungkyunkwan University School of Medicine Seoul 06351 Korea

Department of Neurology Taipei Veterans General Hospital Taipei Taiwan Department of Neurology National Yang Ming University School of Medicine 10466 Taipei Taiwan

Department of Neurosciences Reproductive Sciences and Odontostomathology Federico 2 University Naples 80131 Italy

Department of Pediatric Neurology 2 Faculty of Medicine Charles University Prague and University Hospital Motol Prague 150 06 Czech Republic

Department of Pharmacology Sylvester Comprehensive Cancer Center and Center for Computational Sciences University of Miami Miami FL 33136 USA

Department of Physiology and Biophysics University of Miami Miller School of Medicine Miami FL 33136 USA

DNA Laboratory Department of Pediatric Neurology 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Prague 150 06 Czech Republic

Dr John T Macdonald Foundation Department of Human Genetics John P Hussman Institute for Human Genomics University of Miami Miller School of Medicine Miami FL 33136 USA

Neurogenetic Unit Royal Perth Hospital Perth WA 6000 Australia

Neurogenetics Unit Department of Diagnostic Genomics PathWest Laboratory Medicine QEII Medical Centre Nedlands WA 6009 Australia

The Genesis Project foundation Miami FL 33136 USA

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