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. 2012 Nov 20;79(21):2115-21.
doi: 10.1212/WNL.0b013e3182752c5a. Epub 2012 Oct 17.

PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine

Alice R Gardiner  1 , Kailash P Bhatia, Maria Stamelou, Russell C Dale, Manju A Kurian, Susanne A Schneider, G M Wali, Tim Counihan, Anthony H Schapira, Sian D Spacey, Enza-Maria Valente, Laura Silveira-Moriyama, Hélio A G Teive, Salmo Raskin, Josemir W Sander, Andrew Lees, Tom Warner, Dimitri M Kullmann, Nicholas W Wood, Michael Hanna, Henry Houlden
Affiliations

PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine

Alice R Gardiner et al. Neurology. .

Abstract

Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM).

Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls.

Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone.

Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.

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Figures

Figure
Figure. The structure of the PRRT2 gene and the position of the mutations identified (A) and larger families identified with PRRT2 gene mutations (B)
(A) The structure of the PRRT2 gene and the position of the mutations identified. The PRRT2 gene has 4 exons, exon 1 is noncoding, the gene length is 340 amino acids, 1,020 bp. The start ATG (codon 1) is indicated in the figure and all mutations are labeled from this codon up to the stop codon TGA at 340. Reference sequence NM_145239, Ensemble ENST00000358758. Previously reported mutations are written above the protein in black, and mutations identified here are below in blue. (B) Examples of the families identified with PRRT2 gene mutations. The mutation is given in the proband in the pedigree, −/− indicates no mutation, +/− indicated mutation present.
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