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PRRT2 frameshift mutation reduces its mRNA stability resulting loss of function in paroxysmal kinesigenic dyskinesia.

ABSTRACT: A heterozygous frameshift PRRT2 mutation (c.649_650InsC) has been identified as the major causative mutation in several paroxysmal disorders, including paroxysmal kinesigenic dyskinesia (PKD). Since PKD is an autosomal dominant disorder and since the frameshift mutations of PRRT2 may create a truncated protein, it remains unclear whether this mutation causes toxic gain of function or loss of function. By generating Prrt2 knock-in (KI) mice that express human PRRT2 with the c.649_650InsC mutation and by comparing the phenotypes of Prrt2 KI mice with knockout (KO) mice, we find that both KI and KO mice show the same extents of impaired rotarod and balance beam performance as well as the same sensitivity to seizure induction. Both KI and KO mice show altered formation of SNARE complex and number of synaptic vesicles. In addition, western blotting of KI mouse brain tissues could not detect truncated PRRT2 protein that might be generated by the c.649_650InsC mutation. Moreover, the level of PRRT2 mRNA in KI mice is significantly decreased, recapitulating the reduction of PRRT2 mRNA reported in PKD patients. Furthermore, mutant PRRT2 mRNA is unstable and showed shortened half-life than wild-type PRRT2 mRNA. Our studies suggest that PRRT2 frameshift mutation leads to the loss of function by affecting its mRNA stability, a mechanism that is different from haploinsufficiency due to dysfunctional protein or gain of function caused by truncated protein.

SUBMITTER: Pan Y

PROVIDER: S-EPMC6981028 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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PRRT2 frameshift mutation reduces its mRNA stability resulting loss of function in paroxysmal kinesigenic dyskinesia.

Pan Yongcheng Y Liu Qiong Q Zhang Jennifer J Yang Yang Y Tian Yun Y Zeng Junsheng J Yin Peng P Mei Lin L Xiong Wen-Cheng WC Li Xiao-Jiang XJ Li Shihua S Tang Beisha B

Biochemical and biophysical research communications 20191127 3

A heterozygous frameshift PRRT2 mutation (c.649_650InsC) has been identified as the major causative mutation in several paroxysmal disorders, including paroxysmal kinesigenic dyskinesia (PKD). Since PKD is an autosomal dominant disorder and since the frameshift mutations of PRRT2 may create a truncated protein, it remains unclear whether this mutation causes toxic gain of function or loss of function. By generating Prrt2 knock-in (KI) mice that express human PRRT2 with the c.649_650InsC mutation ...[more]

PMID: 31785815

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Project description:BackgroundParoxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder, characterized by attacks of involuntary movements triggered by sudden action. Variants in proline-rich transmembrane protein 2 (PRRT2) are the most common genetic cause of PKD.ObjectiveThe objective was to investigate the clinical and genetic characteristics of PKD and to establish genotype-phenotype correlations.MethodsWe enrolled 219 PKD patients, documented their clinical information and performed PRRT2 screening using Sanger sequencing. Whole exome sequencing was performed on 49 PKD probands without PRRT2 variants. Genotype-phenotype correlation analyses were conducted on the probands.ResultsAmong 219 PKD patients (99 cases from 39 families and 120 sporadic cases), 16 PRRT2 variants were identified. Nine variants (c.879+4A>G, c.879+5G>A, c.856G>A, c.955G>T, c.884G>C, c.649C>T, c.649dupC, c.649delC and c.696_697delCA) were previously known, while seven were novel (c.367_403del, c.347_348delAA, c.835C>T, c.116dupC, c.837_838insC, c.916_937del and c.902G>A). The mean interval from onset to diagnosis was 7.94 years. Compared to patients without PRRT2 variants, patients with the variants were more likely to have a positive family history, an earlier age of onset and a higher prevalence of falls during pre-treatment attacks (27.14% versus 8.99%, respectively). Patients with truncated PRRT2 variants tend to have bilateral attacks. We identified two transmembrane protein 151A (TMEM151A) variants including a novel variant (c.368G>C) and a reported variant (c.203C>T) in two PRRT2-negative probands with PKD.ConclusionThese findings provide insights on the clinical characteristics, diagnostic timeline and treatment response of PKD patients. PKD patients with truncated PRRT2 variants may tend to have more severe paroxysmal symptoms. This study expands the spectrum of PRRT2 and TMEM151A variants. Carbamazepine and oxcarbazepine are both used as a first-line treatment choice for PKD patients.

Dataset Information

PRRT2 frameshift mutation reduces its mRNA stability resulting loss of function in paroxysmal kinesigenic dyskinesia.

Publications

PRRT2 frameshift mutation reduces its mRNA stability resulting loss of function in paroxysmal kinesigenic dyskinesia.

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