In:
Epilepsia, Wiley, Vol. 59, No. 8 ( 2018-08), p. 1621-1630
Abstract:
To identify the causative gene of autosomal dominant paroxysmal kinesigenic dyskinesia and benign familial infantile seizures ( PKD / BFIS ) in a large Chinese family and explore the potential pathogenic mechanism of a PRRT 2 (proline‐rich transmembrane protein 2) variant. Methods Genetic testing was performed via whole exome sequencing. Western blotting and immunofluorescence were used to analyze the protein expression level and subcellular localization of the PRRT 2 mutant in HeLa cells and N2A cells. Coimmunoprecipitation was conducted to investigate the interaction of the PRRT 2 mutant with syntaxin 1B ( STX 1B). Results In a large Chinese family with autosomal dominant PKD / BFIS showing wide phenotypic heterogeneity, including patients suffering from PKD , BFIS , or epilepsy and asymptomatic variant carriers, a c.621dupA variant in PRRT 2 was identified in the proband and was shown to cosegregate with the phenotype in this family. This variant results in premature termination at codon 224, producing a truncated protein (p.Ser208Ilefs*17) in which the two conserved hydrophobic segments and the cytoplasmic loop are missing. Both the expression and subcellular localization of PRRT 2 are strongly affected by the c.621dupA variant. In addition, we found that PRRT 2 directly interacts with STX 1B, a SNARE protein critical for neurotransmitter release, whereas the truncated variant p.Ser208Ilefs*17 lacking the helix‐loop‐helix domain fails to bind to STX 1B. Significance Our findings identified a PRRT 2 variant in a family with PKD / BFIS and confirmed STX 1B as a new binding partner of PRRT 2, which suggested that the loss of the interaction between PRRT 2 and STX 1B may contribute to the pathogenesis of PKD / BFIS .
Type of Medium:
Online Resource
ISSN:
0013-9580
,
1528-1167
DOI:
10.1111/epi.2018.59.issue-8
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2002194-X
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