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 language | English (US) |
|---|---|
| Pages (from-to) | 505-514 |
| Number of pages | 10 |
| Journal | American Journal of Human Genetics |
| Volume | 102 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2018 |
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Keywords
- ATP1A1
- axonal neuropathy
- Charcot-Marie-Tooth
- CMT
- genetic matchmaking
- Mendelian disease
- Na,K ATPase
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
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 journal › Article
}
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.
AB - 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.
KW - ATP1A1
KW - axonal neuropathy
KW - Charcot-Marie-Tooth
KW - CMT
KW - genetic matchmaking
KW - Mendelian disease
KW - Na,K ATPase
UR - http://www.scopus.com/inward/record.url?scp=85042606258&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042606258&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2018.01.023
DO - 10.1016/j.ajhg.2018.01.023
M3 - Article
C2 - 29499166
AN - SCOPUS:85042606258
VL - 102
SP - 505
EP - 514
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -