Barcia G et al. (2012), De novo gain-of-function KCNT1 channel mutation...

XB-ART-46906

Nat Genet 2012 Nov 01;4411:1255-9. doi: 10.1038/ng.2441.

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

Barcia G , Fleming MR , Deligniere A , Gazula VR , Brown MR , Langouet M , Chen H , Kronengold J , Abhyankar A , Cilio R , Nitschke P , Kaminska A , Boddaert N , Casanova JL , Desguerre I , Munnich A , Dulac O , Kaczmarek LK , Colleaux L , Nabbout R .

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Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. 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.

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Species referenced: Xenopus
Genes referenced: clcn2 kcnq2 kcnq3 kcnt1 scn1a scn2a

References [+] :

Aminkeng, KCNT1 mutations in ADNFLE and MMPSI: a new driver in the etiology and pathophysiology of early-onset epileptic syndromes. 2013, Pubmed