De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

被引：323

作者：

Heinzen, Erin L. ^{[1
,2
]}

Swoboda, Kathryn J. ^{[3
,4
]}

Hitomi, Yuki ^{[1
]}

Gurrieri, Fiorella ^{[5
]}

Nicole, Sophie ^{[6
,7
,8
]}

de Vries, Boukje ^{[9
]}

Tiziano, F. Danilo ^{[5
]}

Fontaine, Bertrand ^{[6
,7
,8
,10
,11
]}

Walley, Nicole M. ^{[1
]}

Heavin, Sinead ^{[12
]}

Panagiotakaki, Eleni ^{[13
]}

Fiori, Stefania ^{[5
]}

Abiusi, Emanuela ^{[5
]}

Di Pietro, Lorena ^{[5
]}

Sweney, Matthew T. ^{[3
]}

Newcomb, Tara M. ^{[3
]}

Viollet, Louis ^{[4
]}

Huff, Chad ^{[14
]}

Jorde, Lynn B. ^{[14
]}

Reyna, Sandra P. ^{[4
]}

Murphy, Kelley J. ^{[4
]}

Shianna, Kevin V. ^{[1
,2
]}

Gumbs, Curtis E. ^{[1
]}

Little, Latasha ^{[1
]}

Silver, Kenneth ^{[15
,16
]}

Ptacek, Louis J. ^{[17
,18
]}

Haan, Joost ^{[19
,20
]}

Ferrari, Michel D. ^{[20
]}

Bye, Ann M. ^{[21
]}

Herkes, Geoffrey K. ^{[22
]}

Whitelaw, Charlotte M. ^{[22
,23
]}

Webb, David ^{[24
]}

Lynch, Bryan J. ^{[25
]}

Uldall, Peter ^{[26
]}

King, Mary D. ^{[25
]}

Scheffer, Ingrid E. ^{[12
,27
,28
]}

Neri, Giovanni ^{[5
]}

Arzimanoglou, Alexis ^{[13
,29
,30
]}

van den Maagdenberg, Arn M. J. M. ^{[9
,20
]}

Sisodiya, Sanjay M. ^{[31
]}

Mikati, Mohamad A. ^{[32
,33
]}

Goldstein, David B. ^{[1
,34
]}

机构：

[1] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC 27708 USA

[2] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA

[3] Univ Utah, Dept Pediat, Salt Lake City, UT USA

[4] Univ Utah, Dept Neurol, Salt Lake City, UT USA

[5] Univ Cattolica Sacro Cuore, Inst Med Genet, Policlin A Gemelli, Rome, Italy

[6] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, Paris, France

[7] INSERM, U975, Paris, France

[8] CNRS, UMR7225, Paris, France

[9] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands

[10] Grp Hosp Pitie Salpetriere, AP HP, Dept Neurol, F-75634 Paris, France

[11] Grp Hosp Pitie Salpetriere, AP HP, Ctr Reference Canalopathies Musculaires, F-75634 Paris, France

[12] Univ Melbourne, Austin Hlth, Dept Med, Melbourne, Vic, Australia

[13] Univ Hosp Lyon HCL, Woman Mother Child Hosp, Epilepsy Sleep & Pediat Neurophysiol Dept, Lyon, France

[14] Univ Utah, Eccles Inst Human Genet, Dept Human Genet, Salt Lake City, UT USA

[15] Univ Chicago, Dept Neurol, Comer Childrens Hosp, Chicago, IL 60637 USA

[16] Univ Chicago, Dept Pediat, Comer Childrens Hosp, Chicago, IL 60637 USA

[17] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA

[18] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA

[19] Rijnland Hosp, Dept Neurol, Leiderdorp, Netherlands

[20] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands

[21] Sydney Childrens Hosp, Dept Paediat Neurol, Randwick, NSW, Australia

[22] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia

[23] Univ Sydney, No Clin Sch, Sydney, NSW 2006, Australia

[24] Our Ladys Childrens Hosp, Dublin, Ireland

[25] Childrens Univ Hosp, Dublin, Ireland

[26] Univ Copenhagen, Rigshosp, Dept Paediat & Adolescent Med, DK-2100 Copenhagen, Denmark

[27] Univ Melbourne, Royal Childrens Hosp, Dept Paediat, Melbourne, Vic, Australia

[28] Florey Neurosci Inst, Melbourne, Vic, Australia

[29] CNRS, INSERM, U1028, Lyon, France

[30] CNRS, UMR 5292, Lyon, France

[31] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, London, England

[32] Duke Univ, Med Ctr, Div Pediat Neurol, Durham, NC USA

[33] Duke Univ, Dept Neurobiol, Durham, NC USA

[34] Duke Univ, Sch Med, Dept Mol Genet & Microbiol, Durham, NC USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 09期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

ONSET DYSTONIA-PARKINSONISM; GENE MUTATION; MIGRAINE; PUMP; PATHOPHYSIOLOGY; GENOMES;

D O I：

10.1038/ng.2358

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.

引用

页码：1030 / +

页数：6

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