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Am J Hum Genet January 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
PMC ID: PMC5985288
Article link: Am J Hum Genet
Grant support: R01 HL131461 NHLBI NIH HHS , R01 NS043259 NINDS NIH HHS , R35 GM119518 NIGMS NIH HHS , R01 NS094388 NINDS NIH HHS , R01 NS043174 NINDS NIH HHS , U54 NS065712 NINDS NIH HHS , K01 NS096778 NINDS NIH HHS , U54 NS092091 NINDS NIH HHS , R01 NS075764 NINDS NIH HHS , R01 GM109762 NIGMS NIH HHS

Genes referenced: atp1a1


Anderson, 2006, Pubmed [+]

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