De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy

被引：363

作者：

Barcia, Giulia ^{[1
,2
]}

Fleming, Matthew R. ^{[3
,4
]}

Deligniere, Aline ^{[1
]}

Gazula, Valeswara-Rao ^{[3
]}

Brown, Maile R. ^{[3
]}

Langouet, Maeva ^{[5
]}

Chen, Haijun ^{[6
]}

Kronengold, Jack ^{[3
]}

Abhyankar, Avinash ^{[7
]}

Cilio, Roberta ^{[8
]}

Nitschke, Patrick ^{[9
]}

Kaminska, Anna ^{[10
]}

Boddaert, Nathalie ^{[11
]}

Casanova, Jean-Laurent ^{[7
]}

Desguerre, Isabelle ^{[1
]}

Munnich, Arnold ^{[5
]}

Dulac, Olivier ^{[1
,2
]}

Kaczmarek, Leonard K. ^{[3
,4
]}

Colleaux, Laurence ^{[5
]}

Nabbout, Rima ^{[1
,2
]}

机构：

[1] Hop Necker Enfants Malad, AP HP, Ctr Reference Epilepsies Rares, Dept Pediat Neurol, Paris, France

[2] Univ Paris 05, Hop Necker Enfants Malad, INSERM, U663, Paris, France

[3] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA

[4] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA

[5] Univ Paris 05, Hop Necker Enfants Malad, INSERM, U781,Inst Imagine, Paris, France

[6] SUNY Albany, Dept Biol Sci, Albany, NY 12222 USA

[7] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA

[8] Bambino Gesu Pediat Hosp, Div Neurol, Rome, Italy

[9] Hop Necker Enfants Malad, Dept Biostat, Paris, France

[10] Hop Necker Enfants Malad, AP HP, Clin Electrophysiol Unit, Paris, France

[11] Hop Necker Enfants Malad, AP HP, Dept Paediat Radiol, Paris, France

来源：

NATURE GENETICS | 2012年 / 44卷 / 11期

基金：

美国国家卫生研究院;

关键词：

ACTIVATED POTASSIUM CHANNEL; AUTISM SPECTRUM DISORDERS; SCN1A MUTATIONS; FOCAL SEIZURES; K+ CHANNELS; SLACK; EPILEPSY; SODIUM; LEVETIRACETAM; PHENOTYPE;

D O I：

10.1038/ng.2441

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay(1). We performed exome sequencing in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non-conducting function, as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a focus for future diagnostic approaches and research for this devastating condition.

引用

页码：1255 / 1259

页数：5

共 39 条

[1] For K+ channels, Na+ is the new Ca2+ [J].