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Am J Hum Genet. 2018 Mar 1;102(3):505-514. doi: 10.1016/j.ajhg.2018.01.023.

Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2.

Author information

1
DNA Laboratory, Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech Republic.
2
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.
3
Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia.
4
Neurogenetic Unit, Royal Perth Hospital, Perth, WA 6000, Australia.
5
Neurogenetics Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia.
6
Department of Neurosciences, Reproductive Sciences and Odontostomathology, Federico II University, Naples 80131, Italy.
7
Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
8
Department of Pediatric Neurology, 2(nd) Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech Republic.
9
Department of Neurology, 2(nd) Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech Republic.
10
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; The Genesis Project foundation, Miami, FL 33136, USA.
11
Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, Department of Neurology, National Yang-Ming University School of Medicine, 10466 Taipei, Taiwan.
12
Department of Pharmacology, Sylvester Comprehensive Cancer Center, and Center for Computational Sciences, University of Miami, Miami, FL 33136, USA.
13
Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
14
Department of Biological Science, Kongju National University, Gongju 32588, Korea.
15
Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
16
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
17
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. Electronic address: szuchner@med.miami.edu.

Abstract

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.

KEYWORDS:

ATP1A1; CMT; Charcot-Marie-Tooth; Mendelian disease; Na(+),K(+) ATPase; axonal neuropathy; genetic matchmaking

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