Journal article
Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2
American journal of human genetics, Vol.102(3), pp.505-514
03/01/2018
DOI: 10.1016/j.ajhg.2018.01.023
PMCID: PMC5985288
PMID: 29499166
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.
Details
- Title: Subtitle
- Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2
- Creators
- Petra Lassuthova - DNA Laboratory, Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech RepublicAdriana P Rebelo - 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, USAGianina Ravenscroft - Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, WA 6009, AustraliaPhillipa J Lamont - Neurogenetic Unit, Royal Perth Hospital, Perth, WA 6000, AustraliaMark R Davis - Neurogenetics Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, AustraliaFiore Manganelli - Department of Neurosciences, Reproductive Sciences and Odontostomathology, Federico II University, Naples 80131, ItalyShawna M Feely - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAChelsea Bacon - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADana Šafka Brožková - DNA Laboratory, Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech RepublicJana Haberlova - Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech RepublicRadim Mazanec - Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech RepublicFeifei Tao - 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, USACima Saghira - 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, USALisa Abreu - 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, USASteve Courel - 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, USAEric Powell - 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, USAElena Buglo - 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, USADana M Bis - 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, USAMegan F Baxter - Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, WA 6009, AustraliaRoyston W Ong - Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, WA 6009, AustraliaLorna Marns - Neurogenetics Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, AustraliaYi-Chung Lee - Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, Department of Neurology, National Yang-Ming University School of Medicine, 10466 Taipei, TaiwanYunhong Bai - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADaniel G Isom - Department of Pharmacology, Sylvester Comprehensive Cancer Center, and Center for Computational Sciences, University of Miami, Miami, FL 33136, USARené Barro-Soria - Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USAKi W Chung - Department of Biological Science, Kongju National University, Gongju 32588, KoreaSteven S Scherer - Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USAH. Peter Larsson - Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USANigel G Laing - Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, WA 6009, AustraliaByung-Ok Choi - Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, KoreaPavel Seeman - DNA Laboratory, Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech RepublicMichael E Shy - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USALucio Santoro - Department of Neurosciences, Reproductive Sciences and Odontostomathology, Federico II University, Naples 80131, ItalyStephan Zuchner - 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
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.102(3), pp.505-514
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.ajhg.2018.01.023
- PMID
- 29499166
- PMCID
- PMC5985288
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Grant note
- name: Australian National Health and Medical Research Council, award: APP1117510; name: Australian National Health and Medical Research Council, award: APP1122952; DOI: 10.13039/501100000925, name: NHMRC, award: APP1080587; DOI: 10.13039/100000002, name: NIH, award: RO1 NS43174, U54 NS065712, RO1 NS094388, R01 GM109762, R01 HL131461, K01 NS096778, R01NS075764, U54NS065712, U54NS092091, U54 NS065712, R35 GM119518; DOI: 10.13039/501100004663, name: Ministry of Science and Technology, Taiwan, award: 105-2628-B-075-002-MY3; name: Judy Seltzer Levenson Memorial Fund for CMT Research; DOI: 10.13039/100002721, name: Charcot-Marie-Tooth Association; DOI: 10.13039/100005202, name: Muscular Dystrophy Association
- Language
- English
- Date published
- 03/01/2018
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984070995402771
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