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Xilin Zhu - One of the best experts on this subject based on the ideXlab platform.

  • PRRT2 deficiency induces Paroxysmal Kinesigenic dyskinesia by influencing synaptic function in the primary motor cortex of rats.
    Neurobiology of disease, 2018
    Co-Authors: Bantong Wang, Xilin Zhu, Ying Liu
    Abstract:

    Proline-rich transmembrane protein 2 (PRRT2) was identified as the causative gene of Paroxysmal Kinesigenic Choreoathetosis (PKC) as well as various other neurological diseases. However, the molecular mechanisms of how mutant PRRT2 leads to abnormal synaptic function and triggers PKC are still obscure. We generated a Prrt2 truncated mutant rat model which shows spontaneous PKC-like attacks with a relative low frequency as well as increased susceptibility to pentylenetetrazol (PTZ)-induced seizures. We demonstrate that PRRT2 is expressed on both pre- and post-synaptic membranes in the M1 cortex. PRRT2 negatively regulates SNARE complex assembly through interaction with SNAP25, STX1A, and VAMP2. In the M1 cortex of the rat model, release of amino acid neurotransmitters is increased. Protein levels of glutamate receptor subunit GRIA1 are significantly increased in PRRT2 mutant rats, while GABA receptor subunits GABRA1 are significantly reduced. Both frequency and amplitude of mEPSC are significantly increased, while amplitude of mIPSC is decreased and the ratio of mEPSC/mIPSC is significantly increased. The balance between excitatory and inhibitory neuronal activity is disrupted, which could lead to abnormal neuronal hyperexcitability. These results provide new insights into the function of PRRT2 in synaptic transmission and movement control, as well as the pathogenic mechanism underlying PKC.

  • Article PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling
    2015
    Co-Authors: Fenghe Niu, Xilin Zhu, Ning Shen, Xiaozhong Peng, Ying Liu
    Abstract:

    Abstract: 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

  • PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling
    International Journal of Molecular Sciences, 2015
    Co-Authors: Fenghe Niu, Xilin Zhu, Ning Shen, Xiaozhong Peng, Ying Liu
    Abstract:

    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

  • Targeted genomic sequencing identifies PRRT2 mutations as a cause of Paroxysmal Kinesigenic Choreoathetosis
    Journal of medical genetics, 2011
    Co-Authors: Xilin Zhu, Xin Wang, Bei Sun, Wei Sun, Bing Feng, Fenghe Niu, Hua Wei
    Abstract:

    Background Paroxysmal Kinesigenic Choreoathetosis (PKC) is characterised by recurrent and brief attacks of involuntary movement, inherited as an autosomal dominant trait with incomplete penetrance. A PKC locus has been previously mapped to the pericentromeric region of chromosome 16 (16p11.2-q12.1), but the causative gene remains unidentified. Methods/results Deep sequencing of this 30 Mb region enriched with array capture in five affected individuals from four Chinese PKC families detected two heterozygous PRRT2 insertions (c.369dupG and c.649dupC), producing frameshifts and premature stop codons (p.S124VfsX10 and p.R217PfsX8, respectively) in two different families. Sanger sequencing confirmed these two mutations and revealed a missense PRRT2 mutation (c.859G/A, p.A287T) in one of the two remaining families. This study also sequenced PRRT2 in 29 sporadic cases affected with PKC and identified mutations in 10 cases, including six with the c.649dupC mutation. Most variants were truncating mutations, consistent with loss-of-function and haploinsufficiency. Conclusion The present study identifies PRRT2 as the gene mutated in a subset of PKC, and suggests that PKC is genetically heterogeneous.

  • Paroxysmal Kinesigenic Choreoathetosis evidence of linkage to the pericentromeric region of chromosome 16 in four chinese families
    European Journal of Neurology, 2010
    Co-Authors: Xin Wang, Xilin Zhu, Nifang Niu, Wei Sun, Hua Wei, W. Mao, Shuying Zhu, Yu Sun, Yunbao Liu, Yan Wang
    Abstract:

    Background:  Paroxysmal Kinesigenic Choreoathetosis (PKC) is an autosomal dominant condition characterized by abnormal involuntary movements precipitated by sudden movement. The pericentromeric region of chromosome 16 has been linked to PKC by several reports. This study was to localize and identify PKC gene in four Chinese PKC families. Methods:  Genetic linkage mapping with eight markers spanning chromosome 16p12-q13 was performed in 43 family members. Genome-wide single nucleotide polymorphism (SNP) scans were performed on four individuals in Family 1 in which infantile convulsion (IC) was co-inherited with PKC. Results:  Individuals in Family 1 presented with both IC and Paroxysmal Choreoathetosis (ICCA), and Families 2, 3, and 4 presented only with PKC. Evidence for linkage was found with a maximum two-point LOD score of 4.89 for D16S690 (θ = 0.0) and a maximum multipoint LOD score was 5.34 between D16S3080 and D16S3136. Haplotype analysis showed the disease locus was between D16S3093 and D16S3057. A total of 84 SNPs spanned on 16q12.1-q13 was not segregated with the PKC phenotype, which defined an unlinked region from rs9933187 to rs8044753. Thus, the critical region of the PKC gene is across the pericentromeric region of chromosome 16, and most likely maps to a region of 20.5 Mb (6.2 cM) between D16S3093 and rs9933187 (16p11.2-q12.1). Conclusion:  The assignment of the locus for PKC to the pericentromeric region of chromosome 16 is confirmed and putatively narrowed in the present study.

Sönke Johannes - One of the best experts on this subject based on the ideXlab platform.

  • event related brain potentials in Paroxysmal Kinesigenic Choreoathetosis
    European Journal of Neurology, 1996
    Co-Authors: Thomas F. Münte, Sönke Johannes
    Abstract:

    Event-related brain potentials (ERPs) were recorded in a 30 year old female patient with familial Kinesigenic Choreoathetosis and a group of control subjects. In line with previous observations the patient exhibited an enhanced amplitude of the early component of the contingent negative variation of the ERP in a two stimulus paradigm. Moreover, a greatly enhanced P3 amplitude was found in auditory and visual classification (oddball) paradigms. These results suggest a general upregulation of widespread subcortical projection systems leading to both, abnormal movements and abnormally high amplitudes of ERPs.

  • Event‐related brain potentials in Paroxysmal Kinesigenic Choreoathetosis
    European Journal of Neurology, 1996
    Co-Authors: Thomas F. Münte, Sönke Johannes
    Abstract:

    Event-related brain potentials (ERPs) were recorded in a 30 year old female patient with familial Kinesigenic Choreoathetosis and a group of control subjects. In line with previous observations the patient exhibited an enhanced amplitude of the early component of the contingent negative variation of the ERP in a two stimulus paradigm. Moreover, a greatly enhanced P3 amplitude was found in auditory and visual classification (oddball) paradigms. These results suggest a general upregulation of widespread subcortical projection systems leading to both, abnormal movements and abnormally high amplitudes of ERPs.

Xin Wang - One of the best experts on this subject based on the ideXlab platform.

  • Targeted genomic sequencing identifies PRRT2 mutations as a cause of Paroxysmal Kinesigenic Choreoathetosis
    Journal of medical genetics, 2011
    Co-Authors: Xilin Zhu, Xin Wang, Bei Sun, Wei Sun, Bing Feng, Fenghe Niu, Hua Wei
    Abstract:

    Background Paroxysmal Kinesigenic Choreoathetosis (PKC) is characterised by recurrent and brief attacks of involuntary movement, inherited as an autosomal dominant trait with incomplete penetrance. A PKC locus has been previously mapped to the pericentromeric region of chromosome 16 (16p11.2-q12.1), but the causative gene remains unidentified. Methods/results Deep sequencing of this 30 Mb region enriched with array capture in five affected individuals from four Chinese PKC families detected two heterozygous PRRT2 insertions (c.369dupG and c.649dupC), producing frameshifts and premature stop codons (p.S124VfsX10 and p.R217PfsX8, respectively) in two different families. Sanger sequencing confirmed these two mutations and revealed a missense PRRT2 mutation (c.859G/A, p.A287T) in one of the two remaining families. This study also sequenced PRRT2 in 29 sporadic cases affected with PKC and identified mutations in 10 cases, including six with the c.649dupC mutation. Most variants were truncating mutations, consistent with loss-of-function and haploinsufficiency. Conclusion The present study identifies PRRT2 as the gene mutated in a subset of PKC, and suggests that PKC is genetically heterogeneous.

  • Paroxysmal Kinesigenic Choreoathetosis evidence of linkage to the pericentromeric region of chromosome 16 in four chinese families
    European Journal of Neurology, 2010
    Co-Authors: Xin Wang, Xilin Zhu, Nifang Niu, Wei Sun, Hua Wei, W. Mao, Shuying Zhu, Yu Sun, Yunbao Liu, Yan Wang
    Abstract:

    Background:  Paroxysmal Kinesigenic Choreoathetosis (PKC) is an autosomal dominant condition characterized by abnormal involuntary movements precipitated by sudden movement. The pericentromeric region of chromosome 16 has been linked to PKC by several reports. This study was to localize and identify PKC gene in four Chinese PKC families. Methods:  Genetic linkage mapping with eight markers spanning chromosome 16p12-q13 was performed in 43 family members. Genome-wide single nucleotide polymorphism (SNP) scans were performed on four individuals in Family 1 in which infantile convulsion (IC) was co-inherited with PKC. Results:  Individuals in Family 1 presented with both IC and Paroxysmal Choreoathetosis (ICCA), and Families 2, 3, and 4 presented only with PKC. Evidence for linkage was found with a maximum two-point LOD score of 4.89 for D16S690 (θ = 0.0) and a maximum multipoint LOD score was 5.34 between D16S3080 and D16S3136. Haplotype analysis showed the disease locus was between D16S3093 and D16S3057. A total of 84 SNPs spanned on 16q12.1-q13 was not segregated with the PKC phenotype, which defined an unlinked region from rs9933187 to rs8044753. Thus, the critical region of the PKC gene is across the pericentromeric region of chromosome 16, and most likely maps to a region of 20.5 Mb (6.2 cM) between D16S3093 and rs9933187 (16p11.2-q12.1). Conclusion:  The assignment of the locus for PKC to the pericentromeric region of chromosome 16 is confirmed and putatively narrowed in the present study.

  • Paroxysmal Kinesigenic Choreoathetosis: evidence of linkage to the pericentromeric region of chromosome 16 in four Chinese families.
    European journal of neurology, 2010
    Co-Authors: Xin Wang, Xilin Zhu, Wei Sun, Hua Wei, W. Mao, Shuying Zhu, Yu Sun
    Abstract:

    Paroxysmal Kinesigenic Choreoathetosis (PKC) is an autosomal dominant condition characterized by abnormal involuntary movements precipitated by sudden movement. The pericentromeric region of chromosome 16 has been linked to PKC by several reports. This study was to localize and identify PKC gene in four Chinese PKC families. Genetic linkage mapping with eight markers spanning chromosome 16p12-q13 was performed in 43 family members. Genome-wide single nucleotide polymorphism (SNP) scans were performed on four individuals in Family 1 in which infantile convulsion (IC) was co-inherited with PKC. Individuals in Family 1 presented with both IC and Paroxysmal Choreoathetosis (ICCA), and Families 2, 3, and 4 presented only with PKC. Evidence for linkage was found with a maximum two-point LOD score of 4.89 for D16S690 (theta = 0.0) and a maximum multipoint LOD score was 5.34 between D16S3080 and D16S3136. Haplotype analysis showed the disease locus was between D16S3093 and D16S3057. A total of 84 SNPs spanned on 16q12.1-q13 was not segregated with the PKC phenotype, which defined an unlinked region from rs9933187 to rs8044753. Thus, the critical region of the PKC gene is across the pericentromeric region of chromosome 16, and most likely maps to a region of 20.5 Mb (6.2 cM) between D16S3093 and rs9933187 (16p11.2-q12.1). The assignment of the locus for PKC to the pericentromeric region of chromosome 16 is confirmed and putatively narrowed in the present study.

  • Localization and mutation detection for Paroxysmal Kinesigenic Choreoathetosis.
    Journal of molecular neuroscience : MN, 2007
    Co-Authors: Bin Feng, Xin Wang, Wei Mao, Xilin Zhu, Bei Sun, Nifang Niu, Yang Liu, Yuping Wang
    Abstract:

    Backgrounds Paroxysmal Kinesigenic Choreoathetosis (PKC) is an autosomal-dominant movement disorder characterized by attacks of Paroxysmal involuntary movements. To date, the causative gene has not been discovered.

F Fazio - One of the best experts on this subject based on the ideXlab platform.

Hua Wei - One of the best experts on this subject based on the ideXlab platform.

  • Targeted genomic sequencing identifies PRRT2 mutations as a cause of Paroxysmal Kinesigenic Choreoathetosis
    Journal of medical genetics, 2011
    Co-Authors: Xilin Zhu, Xin Wang, Bei Sun, Wei Sun, Bing Feng, Fenghe Niu, Hua Wei
    Abstract:

    Background Paroxysmal Kinesigenic Choreoathetosis (PKC) is characterised by recurrent and brief attacks of involuntary movement, inherited as an autosomal dominant trait with incomplete penetrance. A PKC locus has been previously mapped to the pericentromeric region of chromosome 16 (16p11.2-q12.1), but the causative gene remains unidentified. Methods/results Deep sequencing of this 30 Mb region enriched with array capture in five affected individuals from four Chinese PKC families detected two heterozygous PRRT2 insertions (c.369dupG and c.649dupC), producing frameshifts and premature stop codons (p.S124VfsX10 and p.R217PfsX8, respectively) in two different families. Sanger sequencing confirmed these two mutations and revealed a missense PRRT2 mutation (c.859G/A, p.A287T) in one of the two remaining families. This study also sequenced PRRT2 in 29 sporadic cases affected with PKC and identified mutations in 10 cases, including six with the c.649dupC mutation. Most variants were truncating mutations, consistent with loss-of-function and haploinsufficiency. Conclusion The present study identifies PRRT2 as the gene mutated in a subset of PKC, and suggests that PKC is genetically heterogeneous.

  • Paroxysmal Kinesigenic Choreoathetosis evidence of linkage to the pericentromeric region of chromosome 16 in four chinese families
    European Journal of Neurology, 2010
    Co-Authors: Xin Wang, Xilin Zhu, Nifang Niu, Wei Sun, Hua Wei, W. Mao, Shuying Zhu, Yu Sun, Yunbao Liu, Yan Wang
    Abstract:

    Background:  Paroxysmal Kinesigenic Choreoathetosis (PKC) is an autosomal dominant condition characterized by abnormal involuntary movements precipitated by sudden movement. The pericentromeric region of chromosome 16 has been linked to PKC by several reports. This study was to localize and identify PKC gene in four Chinese PKC families. Methods:  Genetic linkage mapping with eight markers spanning chromosome 16p12-q13 was performed in 43 family members. Genome-wide single nucleotide polymorphism (SNP) scans were performed on four individuals in Family 1 in which infantile convulsion (IC) was co-inherited with PKC. Results:  Individuals in Family 1 presented with both IC and Paroxysmal Choreoathetosis (ICCA), and Families 2, 3, and 4 presented only with PKC. Evidence for linkage was found with a maximum two-point LOD score of 4.89 for D16S690 (θ = 0.0) and a maximum multipoint LOD score was 5.34 between D16S3080 and D16S3136. Haplotype analysis showed the disease locus was between D16S3093 and D16S3057. A total of 84 SNPs spanned on 16q12.1-q13 was not segregated with the PKC phenotype, which defined an unlinked region from rs9933187 to rs8044753. Thus, the critical region of the PKC gene is across the pericentromeric region of chromosome 16, and most likely maps to a region of 20.5 Mb (6.2 cM) between D16S3093 and rs9933187 (16p11.2-q12.1). Conclusion:  The assignment of the locus for PKC to the pericentromeric region of chromosome 16 is confirmed and putatively narrowed in the present study.

  • Paroxysmal Kinesigenic Choreoathetosis: evidence of linkage to the pericentromeric region of chromosome 16 in four Chinese families.
    European journal of neurology, 2010
    Co-Authors: Xin Wang, Xilin Zhu, Wei Sun, Hua Wei, W. Mao, Shuying Zhu, Yu Sun
    Abstract:

    Paroxysmal Kinesigenic Choreoathetosis (PKC) is an autosomal dominant condition characterized by abnormal involuntary movements precipitated by sudden movement. The pericentromeric region of chromosome 16 has been linked to PKC by several reports. This study was to localize and identify PKC gene in four Chinese PKC families. Genetic linkage mapping with eight markers spanning chromosome 16p12-q13 was performed in 43 family members. Genome-wide single nucleotide polymorphism (SNP) scans were performed on four individuals in Family 1 in which infantile convulsion (IC) was co-inherited with PKC. Individuals in Family 1 presented with both IC and Paroxysmal Choreoathetosis (ICCA), and Families 2, 3, and 4 presented only with PKC. Evidence for linkage was found with a maximum two-point LOD score of 4.89 for D16S690 (theta = 0.0) and a maximum multipoint LOD score was 5.34 between D16S3080 and D16S3136. Haplotype analysis showed the disease locus was between D16S3093 and D16S3057. A total of 84 SNPs spanned on 16q12.1-q13 was not segregated with the PKC phenotype, which defined an unlinked region from rs9933187 to rs8044753. Thus, the critical region of the PKC gene is across the pericentromeric region of chromosome 16, and most likely maps to a region of 20.5 Mb (6.2 cM) between D16S3093 and rs9933187 (16p11.2-q12.1). The assignment of the locus for PKC to the pericentromeric region of chromosome 16 is confirmed and putatively narrowed in the present study.