PRRT2 Gene Mutations in Indian Paroxysmal Kinesigenic Dyskinesia Patients.
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ABSTRACT:
SUBMITTER: Prabhakara S
PROVIDER: S-EPMC8370144 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2 in the vast majority (24/25) of well-characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. PRRT2 encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture, and mutants associated with PKD/IC lead to dramatically reduced PRRT2 levels, leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC.
| S-EPMC3334308 | biostudies-literature
Project description:This study explored the topological characteristics of brain white matter structural networks in patients with Paroxysmal Kinesigenic Dyskinesia (PKD), and the potential influence of the brain network stability gene PRRT2 on the structural connectome in PKD. Thirty-five PKD patients with PRRT2 mutations (PKD-M), 43 PKD patients without PRRT2 mutations (PKD-N), and 40 demographically-matched healthy control (HC) subjects underwent diffusion tensor imaging. Graph theory and network-based statistic (NBS) approaches were performed; the topological properties of the white matter structural connectome were compared across the groups, and their relationships with the clinical variables were assessed. Both disease groups PKD-M and PKD-N showed lower local efficiency (implying decreased segregation ability) compared to the HC group; PKD-M had longer characteristic path length and lower global efficiency (implying decreased integration ability) compared to PKD-N and HC, independently of the potential effects of medication. Both PKD-M and PKD-N had decreased nodal characteristics in the left thalamus and left inferior frontal gyrus, the alterations being more pronounced in PKD-M patients, who also showed abnormalities in the left fusiform and bilateral middle temporal gyrus. In the connectivity characteristics assessed by NBS, the alterations were more pronounced in the PKD-M group versus HC than in PKD-N versus HC. As well as the white matter alterations in the basal ganglia-thalamo-cortical circuit related to PKD with or without PRRT2 mutations, findings in the PKD-M group of weaker small-worldness and more pronounced regional disturbance show the adverse effects of PRRT2 gene mutations on brain structural connectome.
| S-EPMC7469858 | biostudies-literature
Project description:BACKGROUND:Mutations in the PRRT2 gene have recently been identified in patients with familial paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and patients with sporadic PKD/IC from several ethnic groups. To extend these recent genetic reports, we investigated the frequency and identities of PRRT2 mutations in a cohort of Taiwanese patients with PKD/IC. METHODOLOGY AND PRINCIPAL FINDINGS:We screened all 3 coding exons of PRRT2 for mutations in 28 Taiwanese patients with PKD/IC. Among them, 13 had familial PKD/IC and 15 were apparently sporadic cases. In total, 7 disparate mutations were identified in 13 patients, including 8 familial cases and 5 apparently sporadic cases. The mutations were not present in 500 healthy controls. Four mutations were novel. One patient had a missense mutation and all other patients carried PRRT2 mutations putatively resulting in a protein truncation. Haplotype analysis revealed that 5 of the 7 patients with the PRRT2 p.R217Pfs*8 mutation shared the same haplotype linked to the mutation. CONCLUSIONS AND SIGNIFICANCE:PRRT2 mutations account for 61.5% (8 out of 13) of familial PKD/IC and 33.3% (5 out of 15) of apparently sporadic PKD/IC in the Taiwanese cohort. Most patients with the PRRT2 p.R217Pfs*8 mutation in Taiwan likely descend from a single common ancestor. This study expands the spectrum of PKD/IC-associated PRRT2 mutations, highlights the pathogenic role of PRRT2 mutations in PKD/IC, and suggests genetic heterogeneity within idiopathic PKD.
| S-EPMC3409860 | biostudies-literature
Project description:Paroxysmal kinesigenic dyskinesia (PKD) is an abnormal involuntary movement that is episodic or intermittent, with sudden onset, and the attacks are induced by sudden movement. Mutations in proline-rich transmembrane protein 2 (PRRT2) gene have been implicated in the cause of this disorder. This study presents a case of PKD on the basis of clinical findings supported and evidences obtained through a mutational analysis. Sequencing of all the exons of PRRT2 gene revealed a frameshift mutation (p.R217Pfs*8) in exon 2 and a novel transition mutation (c.244C > T) in 5'-untranslated region (UTR). Though mutations in PRRT2 gene are well-established in PKD, this study for the first time presents a novel transition mutation in the exon 2 region.
| S-EPMC4251026 | biostudies-literature
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.
| S-EPMC10798112 | biostudies-literature
Project description:Mutations in the proline-rich transmembrane protein 2 (PRRT2) are associated with paroxysmal kinesigenic dyskinesia (PKD) and several other paroxysmal neurological diseases, but the PRRT2 function and pathogenic mechanisms remain largely obscure. Here we show that PRRT2 is a presynaptic protein that interacts with components of the SNARE complex and downregulates its formation. Loss-of-function mutant mice showed PKD-like phenotypes triggered by generalized seizures, hyperthermia, or optogenetic stimulation of the cerebellum. Mutant mice with specific PRRT2 deletion in cerebellar granule cells (GCs) recapitulate the behavioral phenotypes seen in Prrt2-null mice. Furthermore, recording made in cerebellar slices showed that optogenetic stimulation of GCs results in transient elevation followed by suppression of Purkinje cell firing. The anticonvulsant drug carbamazepine used in PKD treatment also relieved PKD-like behaviors in mutant mice. Together, our findings identify PRRT2 as a novel regulator of the SNARE complex and provide a circuit mechanism underlying the PRRT2-related behaviors.
| S-EPMC5752836 | biostudies-literature
Project description:BackgroundRecently, heterozygous mutations in PRRT2 (Chr 16p11.2) have been identified in Han Chinese, Japanese and Caucasians with paroxysmal kinesigenic dyskinesia. In previous work, a paroxysmal kinesigenic dyskinesia locus was mapped to Chr 16p11.2 - q11.2 in a multiplex African-American family.MethodsSanger sequencing was used to analyze all four PRRT2 exons for sequence variants in 13 probands (9 Caucasian, 1 Caucasian-Thai, 1 Vietnamese and 2 African-American) with some form of paroxysmal dyskinesia.ResultsOne patient of mixed Caucasian-Thai background and one African-American family harbored the previously described hotspot mutation in PRRT2 (c.649dupC, p.R217Pfs*8). Another African-American family was found to have a novel mutation (c.776dupG, p.E260*). Both of these variants are likely to cause loss-of-function via nonsense-mediated decay of mutant PRRT2 transcripts. All affected individuals had classic paroxysmal kinesigenic dyskinesia phenotypes.ConclusionsHeterozygous PRRT2 gene mutations also cause paroxysmal kinesigenic dyskinesia in African-Americans. The c.649dupC hotspot mutation in PRRT2 is common across racial groups.
| S-EPMC3460747 | biostudies-literature
Project description:AimsPRRT2 was recently identified as a causative gene for paroxysmal kinesigenic dyskinesia (PKD), and the c.649dupC mutation was shown to be a "high frequency" mutation. This mutation was also identified in many sporadic cases. This might be attributed to the incomplete penetrance of c.649dupC. Alternatively, c.649dupC might derive from de novo. The aim of this study is to elucidate the possibility concerning de novo mutagenesis of PRRT2 mutations in PKD.MethodsNine sporadic Chinese PKD patients including one Mongolian patient were recruited. Direct sequencing of PRRT2 was performed in them and their parents. Haplotype analysis was conducted to confirm the biological relationship.ResultsA novel mutation, c.133_136delCCAG, was identified in one Han patient and his unaffected mother. The c.649dupC mutation was detected in another Han patient and his unaffected father. To our interest, c.649dupC was detected in the Mongolian patient but not in his parents. Haplotype analysis confirmed the biological relationship among the trio. No mutations were identified in the remaining six patients.ConclusionThese findings demonstrate the heterogeneity of PKD, and the de novo mutagenesis of PRRT2 gene might indicate the genetic instability of this region.
| S-EPMC6493561 | biostudies-literature
Project description:PRRT2 mutations are the major causative agent of paroxysmal kinesigenic dyskinesia with infantile convulsion (PKD/IC). The study is aimed at screening PRRT2 gene mutations in patients who suffered from PKD/IC in Chinese population. Thirteen Chinese patients with PKD/IC were screened randomly for coding exons of the PRRT2 gene mutation along with 50 ethnically coordinated control people. Nine (2 unaffected) and 4 of the patients showed familial PKD/IC and apparently sporadic cases, respectively. We identified 5 different PRRT2 mutations in 10 individuals, including 8 familial and 2 apparently sporadic cases. However, no mutations were found in the 50 ethnically matched controls. Unknown (novel) NM_145239.2:c.686G>A and previously reported NM_145239.2:c.743G>C variants were identified in two familial and sporadic patients. All affected members of family A showed mutation NM_145239.2:c.650_670delinsCAATGGTGCCACCACTGGGTTA. The previously identified NM_145239.2:c.412 C>G and NM_145239.2:c.709G>A variants are seen in two individuals assessed in family B. Other than the previously identified variants, some of the patients with PRRT2-PKD/IC showed a new PRRT2 substitution variant. Thus, the spectrum of PRRT2 variants is expanded. The possible role and probability of PRRT2 variants involved in PKD/IC are highlighted.
| S-EPMC7251426 | biostudies-literature
Project description:BackgroundMonoallelic pathogenic variants of PRRT2 often result in paroxysmal kinesigenic dyskinesia (PKD). Little is known about health-related quality of life (HrQoL), non-motor manifestations, self-esteem, and stigma in patients with PKD.ObjectivesWe investigated non-motor symptoms and how they related to HrQoL in a genetically homogeneous group of PRRT2-PKD patients. We paid special attention to perceived stigmatization and self-esteem.MethodsWe prospectively enrolled 21 consecutive PKD patients with a pathogenic variant of PRRT2, and 21 healthy controls matched for age and sex. They were evaluated with dedicated standardized tests for non-motor symptoms, HrQoL, anxiety, depression, stigma, self-esteem, sleep, fatigue, pain, and psychological well-being.ResultsPatients reported an alteration of the physical aspects of HrQoL, regardless of the presence of residual paroxysmal episodes. Non-motor manifestations were frequent, and were an important determinant of the alteration of HrQoL. In addition, patients perceived a higher level of stigmatization which positively correlated with a delay in diagnosis (ρ = 0.615, P = 0.003) and the fear of being judged (ρ = 0.452, P = 0.04), but not with the presence of paroxysmal episodes (ρ = 0.203, P = 0.379).ConclusionsOur findings have important implications for care givers concerning patient management and medical education about paroxysmal dyskinesia. PRRT2-PKD patients should be screened for non-motor disorders in routine care. A long history of misdiagnosis may play a role in the high level of perceived stigmatization. Improving knowledge about diagnostic clues suggestive of PKD is mandatory.
| S-EPMC10354617 | biostudies-literature