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

Petra Lassuthova; Adriana P Rebelo; Gianina Ravenscroft; Phillipa J Lamont; Mark R Davis; Fiore Manganelli; Shawna M Feely; Chelsea Bacon; Dana Šafka Brožková; Jana Haberlova; Radim Mazanec; Feifei Tao; Cima Saghira; Lisa Abreu; Steve Courel; Eric Powell; Elena Buglo; Dana M Bis; Megan F Baxter; Royston W Ong; Lorna Marns; Yi-Chung Lee; Yunhong Bai; Daniel G Isom; René Barro-Soria; Ki W Chung; Steven S Scherer; H. Peter Larsson; Nigel G Laing; Byung-Ok Choi; Pavel Seeman; Michael E Shy; Lucio Santoro; Stephan Zuchner

doi:10.1016/j.ajhg.2018.01.023

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

Journal article

Open access

Peer reviewed

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

Petra Lassuthova, Adriana P Rebelo, Gianina Ravenscroft, Phillipa J Lamont, Mark R Davis, Fiore Manganelli, Shawna M Feely, Chelsea Bacon, Dana Šafka Brožková, Jana Haberlova, …

American journal of human genetics, Vol.102(3), pp.505-514

2018-03-01

DOI: https://doi.org/10.1016/j.ajhg.2018.01.023

PMCID: PMC5985288

PMID: 29499166

Abstract

axonal neuropathy

Charcot-Marie-Tooth

ATP1A1

CMT

genetic matchmaking

Mendelian disease

Na+,K+ ATPase

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.79 Molecular & Cell Biology - Physiology; 1.79.874 K-ATPase
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: 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 Republic
Adriana 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, USA
Gianina Ravenscroft - Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia
Phillipa J Lamont - Neurogenetic Unit, Royal Perth Hospital, Perth, WA 6000, Australia
Mark R Davis - Neurogenetics Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia
Fiore Manganelli - Department of Neurosciences, Reproductive Sciences and Odontostomathology, Federico II University, Naples 80131, Italy
Shawna M Feely - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Chelsea Bacon - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Dana Šafka Brožková - DNA Laboratory, Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech Republic
Jana Haberlova - Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech Republic
Radim Mazanec - Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech Republic
Feifei 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, USA
Cima 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, USA
Lisa 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, USA
Steve 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, USA
Eric 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, USA
Elena 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, USA
Dana 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, USA
Megan F Baxter - Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia
Royston W Ong - Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia
Lorna Marns - Neurogenetics Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia
Yi-Chung Lee - Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, Department of Neurology, National Yang-Ming University School of Medicine, 10466 Taipei, Taiwan
Yunhong Bai - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Daniel G Isom - Department of Pharmacology, Sylvester Comprehensive Cancer Center, and Center for Computational Sciences, University of Miami, Miami, FL 33136, USA
René Barro-Soria - Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Ki W Chung - Department of Biological Science, Kongju National University, Gongju 32588, Korea
Steven S Scherer - Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
H. Peter Larsson - Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Nigel G Laing - Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia
Byung-Ok Choi - Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
Pavel Seeman - DNA Laboratory, Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech Republic
Michael E Shy - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Lucio Santoro - Department of Neurosciences, Reproductive Sciences and Odontostomathology, Federico II University, Naples 80131, Italy
Stephan 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
Publication Details: American journal of human genetics, Vol.102(3), pp.505-514
Publisher: Elsevier Inc
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics; Molecular and Cellular Pharmacology Research; Physiology and Biophysics Research
Language: English
Resource Type: Journal article
PMID: 29499166
PMCID: PMC5985288
Record Identifier: 991031576599902976