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Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. 2018
Petra Lassuthova, and
Adriana P Rebelo, and
Gianina Ravenscroft, and
Phillipa J Lamont, and
Mark R Davis, and
Fiore Manganelli, and
Shawna M Feely, and
Chelsea Bacon, and
Dana Šafka Brožková, and
Jana Haberlova, and
Radim Mazanec, and
Feifei Tao, and
Cima Saghira, and
Lisa Abreu, and
Steve Courel, and
Eric Powell, and
Elena Buglo, and
Dana M Bis, and
Megan F Baxter, and
Royston W Ong, and
Lorna Marns, and
Yi-Chung Lee, and
Yunhong Bai, and
Daniel G Isom, and
René Barro-Soria, and
Ki W Chung, and
Steven S Scherer, and
H Peter Larsson, and
Nigel G Laing, and
Byung-Ok Choi, and
Pavel Seeman, and
Michael E Shy, and
Lucio Santoro, and
Stephan Zuchner
DNA Laboratory, Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 150 06, Czech Republic.
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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