PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine.
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.
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, MRC Centre for Neuromuscular Diseases, Children's Hospital at Westmead, University of Sydney, Sydney, Australia.
Alice R
AR
Gardiner
Kailash P
KP
Bhatia
Maria
M
Stamelou
Russell C
RC
Dale
Manju A
MA
Kurian
Susanne A
SA
Schneider
G M
GM
Wali
Tim
T
Counihan
Anthony H
AH
Schapira
Sian D
SD
Spacey
Enza-Maria
EM
Valente
Laura
L
Silveira-Moriyama
Hélio A G
HA
Teive
Salmo
S
Raskin
Josemir W
JW
Sander
Andrew
A
Lees
Tom
T
Warner
Dimitri M
DM
Kullmann
Nicholas W
NW
Wood
Michael
M
Hanna
Henry
H
Houlden
D000293:Adolescent; D000328:Adult; D000368:Aged; D001259:Ataxia / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002819:Chorea / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020325:Migraine with Aura / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C569370:PRRT2 protein, human