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

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... Full description

Journal Title: American journal of human genetics 2018-03-01, Vol.102 (3), p.505-514
Main Author: Lassuthova, Petra
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
CMT
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9297
Link: https://www.ncbi.nlm.nih.gov/pubmed/29499166
Zum Text:
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5985288
title: Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2
format: Article
creator:
  • 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
subjects:
  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • ATP1A1
  • axonal neuropathy
  • Charcot-Marie-Tooth
  • Charcot-Marie-Tooth Disease - genetics
  • Child
  • CMT
  • Family
  • Female
  • Genes, Dominant
  • Genetic aspects
  • genetic matchmaking
  • Genetic research
  • Humans
  • Male
  • Mendelian disease
  • Middle Aged
  • Mutation - genetics
  • Na+,K+ ATPase
  • Pedigree
  • Report
  • Sodium-Potassium-Exchanging ATPase - chemistry
  • Sodium-Potassium-Exchanging ATPase - genetics
  • Young Adult
ispartof: American journal of human genetics, 2018-03-01, Vol.102 (3), p.505-514
description: 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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creatorLassuthova, 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
creatorcontribLassuthova, 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
descriptionAlthough 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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languageeng
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subjectAdult ; Aged ; Aged, 80 and over ; Amino Acid Sequence ; ATP1A1 ; axonal neuropathy ; Charcot-Marie-Tooth ; Charcot-Marie-Tooth Disease - genetics ; Child ; CMT ; Family ; Female ; Genes, Dominant ; Genetic aspects ; genetic matchmaking ; Genetic research ; Humans ; Male ; Mendelian disease ; Middle Aged ; Mutation - genetics ; Na+,K+ ATPase ; Pedigree ; Report ; Sodium-Potassium-Exchanging ATPase - chemistry ; Sodium-Potassium-Exchanging ATPase - genetics ; Young Adult
ispartofAmerican journal of human genetics, 2018-03-01, Vol.102 (3), p.505-514
rights
02018 American Society of Human Genetics
1Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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32018 American Society of Human Genetics. 2018 American Society of Human Genetics
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1Rebelo, Adriana P
2Ravenscroft, Gianina
3Lamont, Phillipa J
4Davis, Mark R
5Manganelli, Fiore
6Feely, Shawna M
7Bacon, Chelsea
8Brožková, Dana Šafka
9Haberlova, Jana
10Mazanec, Radim
11Tao, Feifei
12Saghira, Cima
13Abreu, Lisa
14Courel, Steve
15Powell, Eric
16Buglo, Elena
17Bis, Dana M
18Baxter, Megan F
19Ong, Royston W
20Marns, Lorna
21Lee, Yi-Chung
22Bai, Yunhong
23Isom, Daniel G
24Barro-Soria, René
25Chung, Ki W
26Scherer, Steven S
27Larsson, H. Peter
28Laing, Nigel G
29Choi, Byung-Ok
30Seeman, Pavel
31Shy, Michael E
32Santoro, Lucio
33Zuchner, Stephan
title
0Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2
1American journal of human genetics
addtitleAm J Hum Genet
descriptionAlthough 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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1Rebelo, Adriana P
2Ravenscroft, Gianina
3Lamont, Phillipa J
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5Manganelli, Fiore
6Feely, Shawna M
7Bacon, Chelsea
8Brožková, Dana Šafka
9Haberlova, Jana
10Mazanec, Radim
11Tao, Feifei
12Saghira, Cima
13Abreu, Lisa
14Courel, Steve
15Powell, Eric
16Buglo, Elena
17Bis, Dana M
18Baxter, Megan F
19Ong, Royston W
20Marns, Lorna
21Lee, Yi-Chung
22Bai, Yunhong
23Isom, Daniel G
24Barro-Soria, René
25Chung, Ki W
26Scherer, Steven S
27Larsson, H. Peter
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titleMutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2
authorLassuthova, 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
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3Amino Acid Sequence
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5axonal neuropathy
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7Charcot-Marie-Tooth Disease - genetics
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9CMT
10Family
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12Genes, Dominant
13Genetic aspects
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15Genetic research
16Humans
17Male
18Mendelian disease
19Middle Aged
20Mutation - genetics
21Na+,K+ ATPase
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23Report
24Sodium-Potassium-Exchanging ATPase - chemistry
25Sodium-Potassium-Exchanging ATPase - genetics
26Young Adult
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6Feely, Shawna M
7Bacon, Chelsea
8Brožková, Dana Šafka
9Haberlova, Jana
10Mazanec, Radim
11Tao, Feifei
12Saghira, Cima
13Abreu, Lisa
14Courel, Steve
15Powell, Eric
16Buglo, Elena
17Bis, Dana M
18Baxter, Megan F
19Ong, Royston W
20Marns, Lorna
21Lee, Yi-Chung
22Bai, Yunhong
23Isom, Daniel G
24Barro-Soria, René
25Chung, Ki W
26Scherer, Steven S
27Larsson, H. Peter
28Laing, Nigel G
29Choi, Byung-Ok
30Seeman, Pavel
31Shy, Michael E
32Santoro, Lucio
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1Rebelo, Adriana P
2Ravenscroft, Gianina
3Lamont, Phillipa J
4Davis, Mark R
5Manganelli, Fiore
6Feely, Shawna M
7Bacon, Chelsea
8Brožková, Dana Šafka
9Haberlova, Jana
10Mazanec, Radim
11Tao, Feifei
12Saghira, Cima
13Abreu, Lisa
14Courel, Steve
15Powell, Eric
16Buglo, Elena
17Bis, Dana M
18Baxter, Megan F
19Ong, Royston W
20Marns, Lorna
21Lee, Yi-Chung
22Bai, Yunhong
23Isom, Daniel G
24Barro-Soria, René
25Chung, Ki W
26Scherer, Steven S
27Larsson, H. Peter
28Laing, Nigel G
29Choi, Byung-Ok
30Seeman, Pavel
31Shy, Michael E
32Santoro, Lucio
33Zuchner, Stephan
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abstractAlthough 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.
copUnited States
pubElsevier Inc
pmid29499166
doi10.1016/j.ajhg.2018.01.023
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