PRRT2 Mutations Are Related to Febrile Seizures  in Epileptic Patients

He, Zhengwen; Qu, Jian; Zhang, Ying; Mao, Chen-Xue; Wang, Zhibin; Mao, Xiao‐Yuan; Deng, Zhiyong; Zhou, Boting; Yin, Ji‐Ye; Long, Hongyu; Xiao, Bo; Zhang, Yu; Zhou, Hong‐Hao; Liu, Zhao‐Qian

doi:10.3390/ijms151223408

Cited by 19 publications

(10 citation statements)

References 29 publications

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“…PRRT2 mutations are involved in many disorders including PKC, benign familial infantile epilepsy (BFIE, MIM 605751), infantile convulsions with choreoathetosis (ICCA, MIM 602066) [ 23 ], hemiplegic and regular migraines, paroxysmal non-kinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia (PED), childhood absence epilepsy, febrile seizures both in family cases [ 24 ] and sporadic cases [ 25 ] and episodic ataxia [ 26 ]. Meanwhile, homozygous PRRT2 mutations have been more frequently associated with intellectual disabilities [ 23 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling

Niu

Zhu

et al. 2015

IJMS

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Paroxysmal kinesigenic choreoathetosis (PKC) is an inherited disease of the nervous system. We previously identified PRRT2 as the causative gene of PKC. However, as little is known about the function of PRRT2, elucidating its function will benefit not only PKC studies, but also many other related disorders. Here, we reveal higher levels of glutamate in the plasma of PKC patients and the culture medium of neurons following knock-out Prrt2 expression. Using double immunostaining assays we confirm Prrt2 is located at the glutamatergic neurons in accordance with its function. Our co-immunoprecipitation assays reveal mutant PRRT2 interferes with SNAP25 and GRIA1 interactions, respectively. Furthermore, using live-labeling techniques, we confirmed co-transfection with mutant PRRT2 caused an increase in GRIA1 distribution on the cell surface. Therefore, our results suggest that mutant PRRT2, probably through its weakened interaction with SNAP25, affects glutamate signaling and glutamate receptor activity, resulting in the increase of glutamate release and subsequent neuronal hyperexcitability.

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Section: Discussionmentioning

confidence: 99%

PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling

Niu

Zhu

et al. 2015

IJMS

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“…GABRAG2 variants (rs211037, rs210987, rs440218, rs2422106, rs211014, and rs401750) and several PRRT2 mutations (c.649delC (p.R217Efs*12), c.649_650insC (p.R217Pfs*8), c.412C>G (p.Pro138Ala), c.439G>C (p.Asp147His), and c.623C>A (p.Ser208Tyr)) are associated with febrile seizures [272]. There is a clear association of rs211037 with epilepsy in Asian patients and of rs211037-rs210987 and rs2422106-rs211014-rs401750 haplotypes with susceptibility to symptomatic epilepsy in Chinese [273].…”

Section: Epilepsymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

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“…In resent decades, high-throughput sequencing has identified mutations in the PRRT2 gene as the leading cause for varieties of paroxysmal diseases besides PKD and > 50 different PRRT2 mutations have been documented [ 20 , 53 , 54 ]. To date, heterozygous PRRT2 mutations have been found in a multitude of patients with BFIE [ 20 ], ICCA [ 20 , 53 ], Paroxysmal Non-Kinesigenic Dyskinesia (PNKD) [ 55 ], Paroxysmal Exertion-induced Dyskinesia (PED) [ 56 ], childhood absence epilepsy and febrile seizures [ 57 , 58 ]. Besides, homozygous PRRT2 mutations have been mainly associated with intellectual disabilities [ 20 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Aberrant transcriptional networks in step-wise neurogenesis of paroxysmal kinesigenic dyskinesia-induced pluripotent stem cells

Zhang

et al. 2016

Oncotarget

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Paroxysmal kinesigenic dyskinesia (PKD) is an episodic movement disorder with autosomal-dominant inheritance and marked variability in clinical manifestations.Proline-rich transmembrane protein 2 (PRRT2) has been identified as a causative gene of PKD, but the molecular mechanism underlying the pathogenesis of PKD still remains a mystery. The phenotypes and transcriptional patterns of the PKD disease need further clarification. Here, we report the generation and neural differentiation of iPSC lines from two familial PKD patients with c.487C>T (p. Gln163X) and c.573dupT (p. Gly192Trpfs*8) PRRT2 mutations, respectively. Notably, an extremely lower efficiency in neural conversion from PKD-iPSCs than control-iPSCs is observed by a step-wise neural differentiation method of dual inhibition of SMAD signaling. Moreover, we show the high expression level of PRRT2 throughout the human brain and the expression pattern of PRRT2 in other human tissues for the first time. To gain molecular insight into the development of the disease, we conduct global gene expression profiling of PKD cells at four different stages of neural induction and identify altered gene expression patterns, which peculiarly reflect dysregulated neural transcriptome signatures and a differentiation tendency to mesodermal development, in comparison to control-iPSCs. Additionally, functional and signaling pathway analyses indicate significantly different cell fate determination between PKD-iPSCs and control-iPSCs. Together, the establishment of PKD-specific in vitro models and the illustration of transcriptome features in PKD cells would certainly help us with better understanding of the defects in neural conversion as well as further investigations in the pathogenesis of the PKD disease.

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PRRT2 Mutations Are Related to Febrile Seizures in Epileptic Patients

Cited by 19 publications

References 29 publications

PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling

PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Aberrant transcriptional networks in step-wise neurogenesis of paroxysmal kinesigenic dyskinesia-induced pluripotent stem cells

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