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

作者：Lassuthova, Petra; Rebelo, Adriana P.; Ravenscroft, Gianina; Lamont, Phillipa J.; Davis, Mark R.; Manganelli, Fiore; Feely, Shawna M.; Bacon, Chelsea; Brozkova, Dana Safka; 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, Rene; Chung, Ki W.; Scherer, Steven S.; Larsson, H. Peter; Laing, Nigel G.

来源：American Journal of Human Genetics, 2018, 102(3): 505-514.

DOI：10.1016/j.ajhg.2018.01.023

• FAMILIAL HEMIPLEGIC MIGRAINE
• CMT NEUROPATHY SCORE
• NERVOUS-SYSTEM
• ALPHA-SUBUNIT
• K+-ATPASE
• DISEASE
• NA+
• NA+,K+-ATPASE
• NA,K-ATPASE
• EXPRESSION

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.

• 出版日期2018-3-1
• 单位河北医科大学