PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome

Abstract

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).

Figure 1

Locations of the Five Mutations in the PRRT2 Sequence (A) Sequence traces showing the five mutations identified in the 19 BFIE- and ICCA-affected families are compared to wild-type traces. (B) Gene structure of the coding exons of PRRT2 shows the locations of the five mutations in BFIE- and ICCA-affected families. (C) The structure of PRRT2 shows the locations of the five mutations. The transmembrane (TM) domains are indicated in purple. In (B) and (C), the frameshift mutations are marked in light blue, the splice-site mutations in dark blue, and the missense mutation in pink. The lines between (B) and (C) indicate which regions of the protein are coded by the three coding exons.

Figure 2

Pedigrees of Families with PRRT2 Mutations Pedigrees of the 19 families affected by BFIE or ICCA show the segregation of the PRRT2 mutation within each family. Individuals with a PRRT2 mutation are indicated by m/+, and individuals tested for mutations and found to be negative are indicated by +/+. Individuals for whom the presence of a mutation was inferred on the basis of its presence in relatives are indicated by (m/+). Four additional families in which no mutation was detected are not shown.

Figure 3

Expression of Prrt2 in the Murine Brain Prrt2 is expressed in the murine brain after birth. (A–E) In situ hybridization analysis of Prrt2 expression in P21 sagittal (A and B) and P46 coronal (D and E) mouse brain sections. Robust, widespread expression was detected in the cerebral cortex (Cx) and caudate putamen (CPu) at P21 (A) and P46 (D). No signal was generated by the sense control probe (B–E). Nissl staining of flanking sections shows cell bodies (C–F). The scale bar represents 0.5 mm.