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 & 14 others 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

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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.

Original languageEnglish
Pages (from-to)505-514
Number of pages10
JournalAmerican Journal of Human Genetics
Volume102
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018

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Axons
Tooth
Mutation
Information Dissemination
Genetic Association Studies
Peripheral Nervous System Diseases
Ouabain
Pedigree
Myelin Sheath
Xenopus
Peripheral Nerves
Oocytes
Electrodes
Nucleotides
Phosphorylation
Genes
Therapeutics
sodium-translocating ATPase

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Lassuthova, Petra ; Rebelo, Adriana P. ; Ravenscroft, Gianina ; Lamont, Phillipa J. ; Davis, Mark R. ; Manganelli, Fiore ; Feely, Shawna M. ; Bacon, Chelsea ; Brožková, Dana Šafka ; Haberlova, Jana ; Mazanec, Radim ; Tao, Feifei ; Saghira, Cima ; Abreu, Lisa ; Courel, Steve ; Powell, Eric ; Buglo, Elena ; Bis, Dana M. ; Baxter, Megan F. ; Ong, Royston W. ; Marns, Lorna ; Lee, Yi Chung ; Bai, Yunhong ; Isom, Daniel G. ; Barro-Soria, René ; Chung, Ki W. ; Scherer, Steven S. ; Larsson, H. Peter ; Laing, Nigel G. ; Choi, Byung Ok ; Seeman, Pavel ; Shy, Michael E. ; Santoro, Lucio ; Zuchner, Stephan. / Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. In: American Journal of Human Genetics. 2018 ; Vol. 102, No. 3. pp. 505-514.
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keywords = "ATP1A1, axonal neuropathy, Charcot-Marie-Tooth, CMT, genetic matchmaking, Mendelian disease, Na,K ATPase",
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Lassuthova, P, Rebelo, AP, Ravenscroft, G, Lamont, PJ, Davis, MR, Manganelli, F, Feely, SM, Bacon, C, Brožková, DŠ, Haberlova, J, Mazanec, R, Tao, F, Saghira, C, Abreu, L, Courel, S, Powell, E, Buglo, E, Bis, DM, Baxter, MF, Ong, RW, Marns, L, Lee, YC, Bai, Y, Isom, DG, Barro-Soria, R, Chung, KW, Scherer, SS, Larsson, HP, Laing, NG, Choi, BO, Seeman, P, Shy, ME, Santoro, L & Zuchner, S 2018, 'Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2' American Journal of Human Genetics, vol. 102, no. 3, pp. 505-514. https://doi.org/10.1016/j.ajhg.2018.01.023

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

In: American Journal of Human Genetics, Vol. 102, No. 3, 01.03.2018, p. 505-514.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2

AU - Lassuthova, Petra

AU - Rebelo, Adriana P.

AU - Ravenscroft, Gianina

AU - Lamont, Phillipa J.

AU - Davis, Mark R.

AU - Manganelli, Fiore

AU - Feely, Shawna M.

AU - Bacon, Chelsea

AU - Brožková, Dana Šafka

AU - Haberlova, Jana

AU - Mazanec, Radim

AU - Tao, Feifei

AU - Saghira, Cima

AU - Abreu, Lisa

AU - Courel, Steve

AU - Powell, Eric

AU - Buglo, Elena

AU - Bis, Dana M.

AU - Baxter, Megan F.

AU - Ong, Royston W.

AU - Marns, Lorna

AU - Lee, Yi Chung

AU - Bai, Yunhong

AU - Isom, Daniel G.

AU - Barro-Soria, René

AU - Chung, Ki W.

AU - Scherer, Steven S.

AU - Larsson, H. Peter

AU - Laing, Nigel G.

AU - Choi, Byung Ok

AU - Seeman, Pavel

AU - Shy, Michael E.

AU - Santoro, Lucio

AU - Zuchner, Stephan

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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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KW - ATP1A1

KW - axonal neuropathy

KW - Charcot-Marie-Tooth

KW - CMT

KW - genetic matchmaking

KW - Mendelian disease

KW - Na,K ATPase

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