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Am J Hum Genet
2018 Mar 01;1023:505-514. doi: 10.1016/j.ajhg.2018.01.023.
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Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2.
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
.
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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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