PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine

Abstract

Objective: Whole genome sequencing and the screening of 103 families recently led us to identify PRRT2 (proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKD/IC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKD/IC or PKD/IC with migraine.

Methods: We performed Sanger sequencing of all PRRT2 coding exons and of exon-intron boundaries in the probands and in their relatives whenever appropriate.

Results: Two known and 2 novel PRRT2 mutations were detected in 18 families. The p.R217Pfs*8 recurrent mutation was found in ≈50% of typical PKD/IC, and the unreported p.R145Gfs*31 in one more typical family. PRRT2 mutations were also found in PKD/IC with migraine: p.R217Pfs*8 cosegregated with PKD associated with HM in one family, and was also detected in one IC patient having migraine with aura, in related PKD/IC familial patients having migraine without aura, and in one sporadic migraineur with abnormal MRI. Previously reported p.R240X was found in one patient with PKD with migraine without aura. The novel frameshift p.S248Afs*65 was identified in a PKD/IC family member with IC and migraine with aura.

Conclusions: We extend the spectrum of PRRT2 mutations and phenotypes to HM and to other types of migraine in the context of PKD/IC, and emphasize the phenotypic pleiotropy seen in patients with PRRT2 mutations.

Figure 1. PRRT2 mutations in 12 families with typical PKD/IC

Females are represented by circles, males by squares. Left half-filled symbols are patients with paroxysmal kinesigenic dyskinesia (PKD). Right half-filled symbols are patients with infantile convulsions (IC). Empty symbols are unaffected individuals. Family number is indicated at the top of each pedigree. DNA from family members with no indication on the mutation status was not available. wt = wild-type. For convenience, names of frameshift mutations have been simplified (R217fs is p.R217Pfs*8, R145fs is p.R145Gfs*31).

Figure 2. PRRT2 mutations in 6 PKD/IC pedigrees with various types of migraine

Females are represented by circles, males by squares. Top left quarter-filled symbols are patients with paroxysmal kinesigenic dyskinesia (PKD). Top right quarter-filled symbols are patients with infantile convulsions (IC). Bottom left quarter-filled symbols indicate patients with generalized tonic-clonic seizures. Bottom right quarter-filled gray symbols are patients with various types of migraine: without aura (P0113, P0115, P4604), with visual aura (P0111, P0116-12), hemiplegic (P2315). Empty symbols are unaffected individuals. Family number is indicated at the top of each pedigree. DNAs from family members with no indication on the mutation status were not available. wt = wild-type. For convenience, names of frameshift mutations have been simplified (R217fs is p.R217Pfs*8, S248fs is p.S248Afs*65).

Figure 3. Four frameshift and nonsense PRRT2 mutations detected in the present study

The PRRT2 protein is from N to C-terminus. Locations of the proline-rich (PR) and transmembrane (TM) domains and of the extracellular (EXT) and intracellular (ITC) parts are indicated. Sequencing traces (both strands) corresponding to each mutation reported here (red asterisks) are shown. The locations of other PRRT2 mutations reported so far^– are indicated from N to C-terminus. Green asterisks: p.S124Vfs*10, p.Q163X, p.S172Rfs*3, p.E173X, p.A211Sfs*14, p.S317N, p.V325Sfs*12, p.I327Ifs*14; green arrow (splice site mutations): c.879+1G>T, c.879+5G>A. aa = aminoacid.