التفاصيل البيبلوغرافية
| العنوان: |
Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. |
| المؤلفون: |
Lassuthova, Petra1,2, Rebelo, Adriana P.2,3, Ravenscroft, Gianina2,4, Lamont, Phillipa J.5, Davis, Mark R.6, Manganelli, Fiore7, Feely, Shawna M.8, Bacon, Chelsea8, Brožková, Dana Šafka1, Haberlova, Jana6, Mazanec, Radim9, Feifei Tao3, Saghira, Cima3, Abreu, Lisa3, Courel, Steve3, Powell, Eric3,10, Buglo, Elena3, Bis, Dana M.3, Baxter, Megan F.4, Ong, Royston W.4 |
| المصدر: |
American Journal of Human Genetics. Mar2018, Vol. 102 Issue 3, p505-514. 10p. |
| مصطلحات موضوعية: |
*GENETIC mutation, *CHARCOT-Marie-Tooth disease, *AXONS, *MYELIN sheath, *PHOSPHORYLATION |
| مستخلص: |
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 alphal 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.l801_1802delinsTT (p.Asp601Phe), c,1798C>G (p.Pro600Ala), c,1798C>A (p.Pro600Thr), and c.2432A>C (p.Asp811 Ala), 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 Xenopits 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+,K4 pump. Five mutants fail 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. [ABSTRACT FROM AUTHOR] |
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