@article{eed74eb233934b23876b05024bde4e4c,
title = "Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2",
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",
author = "Petra Lassuthova and Rebelo, {Adriana P.} and Gianina Ravenscroft and Lamont, {Phillipa J.} and Davis, {Mark R.} and Fiore Manganelli and Feely, {Shawna M.} and Chelsea Bacon and Bro{\v z}kov{\'a}, {Dana {\v S}afka} 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 Bis, {Dana M.} and Baxter, {Megan F.} and Ong, {Royston W.} and Lorna Marns and Lee, {Yi Chung} and Yunhong Bai and Isom, {Daniel G.} and Ren{\'e} Barro-Soria and Chung, {Ki W.} and Scherer, {Steven S.} and Larsson, {H. Peter} and Laing, {Nigel G.} and Choi, {Byung Ok} and Pavel Seeman and Shy, {Michael E.} and Lucio Santoro and Stephan Zuchner",
note = "Funding Information: This work was supported by MH CR AZV 16-30206A and DRO 00064203 (to P.L. and P.S.); Australian National Health and Medical Research Council (NHMRC) Fellowship APP1117510 (to N.L.); Australian National Health and Medical Research Council (NHMRC) Fellowship APP1122952 (to G.R.); NHMRC Project Grant APP1080587 (to N.L.), NIH ( RO1 NS43174 , U54 NS065712 to S.S.S.; RO1 NS094388 to B.-O.C.; R01 GM109762 , R01 HL131461 to H.P.L.; K01 NS096778 to R.B.-S.; R01NS075764 , U54NS065712 , and U54NS092091 to S.Z.; U54 NS065712 to M.S.; R35 GM119518 to D.G.I.), Ministry of Science and Technology, Taiwan ( 105-2628-B-075-002-MY3 to Y.-C.L.), the Judy Seltzer Levenson Memorial Fund for CMT Research , the Charcot-Marie-Tooth Association , and the Muscular Dystrophy Association . We thank C. Kleinberg and Dr. E. Arroyo for confocal images and Dr. Pressley for the rabbit antiserum against ATP1A1. We thank Dr. Pablo Artigas for the human wild-type ATP1A1 and beta1 subunits for Xenopus oocyte expression and help with Xenopus oocyte recordings. ",
year = "2018",
month = mar,
day = "1",
doi = "10.1016/j.ajhg.2018.01.023",
language = "English (US)",
volume = "102",
pages = "505--514",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",
}