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Am J Hum Genet. March 1, 2018; 102 (3): 505-514.

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 .

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.

PubMed ID: 29499166
Article link: Am J Hum Genet.

Genes referenced: atp1a1


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