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

被引：60

作者：

Lassuthova, Petra ^{[1
,2
]}

Rebelo, Adriana P. ^{[3
]}

Ravenscroft, Gianina ^{[4
,5
]}

Lamont, Phillipa J. ^{[6
]}

Davis, Mark R. ^{[7
]}

Manganelli, Fiore ^{[8
]}

Feely, Shawna M. ^{[17
]}

Bacon, Chelsea ^{[17
]}

Brozkova, Dana Safka ^{[1
,2
]}

Haberlova, Jana ^{[2
,18
]}

Mazanec, Radim ^{[2
,20
]}

Tao, Feifei ^{[3
]}

Saghira, Cima ^{[3
]}

Abreu, Lisa ^{[3
]}

Courel, Steve ^{[3
]}

Powell, Eric ^{[3
,9
]}

Buglo, Elena ^{[3
]}

Bis, Dana M. ^{[3
]}

Baxter, Megan F. ^{[4
,5
]}

Ong, Royston W. ^{[4
,5
]}

Marns, Lorna ^{[7
]}

Lee, Yi-Chung ^{[10
,11
]}

Bai, Yunhong ^{[17
]}

Isom, Daniel G. ^{[12
,13
]}

Barro-Soria, Rene ^{[15
]}

Chung, Ki W. ^{[19
]}

Scherer, Steven S. ^{[14
]}

Larsson, H. Peter ^{[15
]}

Laing, Nigel G. ^{[4
,5
]}

Choi, Byung-Ok ^{[16
]}

Seeman, Pavel ^{[1
,2
]}

Shy, Michael E. ^{[17
]}

Santoro, Lucio ^{[8
]}

Zuchner, Stephan ^{[3
]}

机构：

[1] Charles Univ Prague, Fac Med 2, Dept Pediat Neurol, DNA Lab, Prague 15006, Czech Republic

[2] Univ Hosp Motol, Prague 15006, Czech Republic

[3] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL 33136 USA

[4] Univ Western Australia, Med Res Ctr, Nedlands, WA 6009, Australia

[5] Harry Perkins Inst Med Res, Nedlands, WA 6009, Australia

[6] Royal Perth Hosp, Neurogenet Unit, Perth, WA 6000, Australia

[7] QEII Med Ctr, PathWest Lab Med, Dept Diagnost Genom, Neurogenet Unit, Nedlands, WA 6009, Australia

[8] Univ Naples Federico II, Dept Neurosci Reprod Sci & Odontostomathol, I-80131 Naples, Italy

[9] Genesis Project Fdn, Miami, FL 33136 USA

[10] Taipei Vet Gen Hosp, Dept Neurol, Taipei, Taiwan

[11] Natl Yang Ming Univ, Dept Neurol, Sch Med, Taipei 10466, Taiwan

[12] Univ Miami, Sylvester Comprehens Canc Ctr, Dept Pharmacol, Miami, FL 33136 USA

[13] Univ Miami, Ctr Computat Sci, Miami, FL 33136 USA

[14] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA

[15] Univ Miami, Miller Sch Med, Dept Physiol & Biophys, Miami, FL 33136 USA

[16] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurol, Seoul 06351, South Korea

[17] Univ Iowa, Dept Neurol, Carver Coll Med, Iowa City, IA 52242 USA

[18] Charles Univ Prague, Fac Med 2, Dept Pediat Neurol, Prague 15006, Czech Republic

[19] Kongju Natl Univ, Dept Biol Sci, Gongju 32588, South Korea

[20] Charles Univ Prague, Fac Med 2, Dept Neurol, Prague 15006, Czech Republic

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2018年 / 102卷 / 03期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

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

D O I：

10.1016/j.ajhg.2018.01.023

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：505 / 514

页数：10

共 31 条

[1] Mutations in the Na+/K+-ATPase α3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism [J].