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Case Reports
. 2018 Feb 1;4(1):a002287.
doi: 10.1101/mcs.a002287. Print 2018 Feb.

A Novel PRRT2 Pathogenic Variant in a Family With Paroxysmal Kinesigenic Dyskinesia and Benign Familial Infantile Seizures

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Free PMC article
Case Reports

A Novel PRRT2 Pathogenic Variant in a Family With Paroxysmal Kinesigenic Dyskinesia and Benign Familial Infantile Seizures

Jacqueline G Lu et al. Cold Spring Harb Mol Case Stud. .
Free PMC article

Abstract

Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent attacks of dyskinetic movements without alteration of consciousness that are often triggered by the initiation of voluntary movements. Whole-exome sequencing has revealed a cluster of pathogenic variants in PRRT2 (proline-rich transmembrane protein), a gene with a function in synaptic regulation that remains poorly understood. Here, we report the discovery of a novel PRRT2 pathogenic variant inherited in an autosomal dominant pattern in a family with PKD and benign familial infantile seizures (BFIS). After targeted Sanger sequencing did not identify the presence of previously described PRRT2 pathogenic variants, we carried out whole-exome sequencing in the proband and her affected paternal grandfather. This led to the discovery of a novel PRRT2 variant, NM_001256442:exon3:c.C959T/NP_660282.2:p.A320V, altering an evolutionarily conserved alanine at the amino acid position 320 located in the M2 transmembrane region. Sanger sequencing further confirmed the presence of this variant in four affected family members (paternal grandfather, father, brother, and proband) and its absence in two unaffected ones (paternal grandmother and mother). This newly found variant further reinforces the importance of PRRT2 in PKD, BFIS, and possibly other movement disorders. Future functional studies using animal models and human pluripotent stem cell models will provide new insights into the role of PRRT2 and the significance of this variant in regulating neural development and/or function.

Keywords: ataxia; autism; extrapyramidal dyskinesia; focal autonomic seizures without altered responsiveness; infantile spasms; intellectual disability, profound; migraine without aura; paroxysmal dyskinesia.

Figures

Figure 1.
Figure 1.
Pedigree of the affected family indicates a dominant inheritance pattern with distinct clinical phenotypes. (A) Pedigree with individuals numbered. (B) Affected individuals with their known clinical phenotypic manifestations. At the time of this study, III-2 has not reached the age for the manifestation of PKD.
Figure 2.
Figure 2.
Sanger sequencing of the PRRT2 gene in the proband excludes the presence of common variants. (A) PRRT2 gene structure with exons/introns demarcated. Locations of the PCR primers are indicated. (B) Gel electrophoresis images show the PCR products amplified from the proband genomic DNA with various pairs of primers. (C) Representative traces from Sanger sequencing show the absence of two commonly detected PRRT2 variants in the proband.
Figure 3.
Figure 3.
Segregation of a novel pathogenic PRRT2 variant uncovered via whole-exome sequencing with phenotypic characteristics of PKD and BFIS. Representative traces from Sanger sequencing show the 100% concordance of the c.959C>T/p.A320V variant with the affected individuals in the family.
Figure 4.
Figure 4.
The location of alanine 320 in the PRRT2 protein and its evolutionary conservation. (A) A structural model of the PRRT2 protein transmembrane domains (residues 261–340). The protein backbone is shown as a schematic, with alanine residues colored in red. Dashed lines indicate putative membrane limits. The structural model was from Rossi et al. (2016). (B) Maximum likelihood phylogenic tree of the representative PRRT2 orthologs across vertebrates. The tree is drawn to scale, with branch lengths measured in the number of substitutions per site. All positions containing gaps were eliminated; there were a total of 146 positions in the final data set. (C) Multiple protein sequence alignment of the PRRT2 sequence region encompassing the A320 residue in representative vertebrate species. Conserved Ala in position 320 is highlighted in yellow, and Ser, which is conserved in this position in bony fishes, is highlighted in green. Substitutions in position 307 are highlighted in blue. An alignment of this region in all detected PPR2 homologs is shown in Supplemental Figure S2.

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