Disease:


  • OMIM ID: 614386 . 614386
  • OMIM diseaseName:
  • OMIM diseaseClinical_Synopsis:
  • OMIM diseaseText: CLONING Chen et al. (2011) identified PRRT2 within a region of chromosome 16 linked to the paroxysmal kinesigenic dyskinesia locus (EKD1; 128200). The deduced 340-amino acid protein has a proline-rich domain in its N-terminal half and 2 transmembrane domains in its C-terminal half. RT-PCR of mouse tissues detected high Prrt2 expression in brain and spinal cord, with negligible expression in all other tissues examined. Prrt2 expression in mouse was low prior to embryonic day 16, after which it increased, peaked at postnatal day 14, and declined in adult. RT-PCR and in situ hybridization of postnatal day-14 mouse brain revealed high Prrt2 expression in cerebral cortex, hippocampus, and cerebellum, with enrichment in cortical layers of cerebral cortex, as well as in granule cells and Purkinje cell layers of cerebellum. Fluorescence-tagged PRRT2 was expressed in the membrane of transfected COS-7 cells. Heron et al. (2012) found that Prrt2 was widely expressed in the mouse brain, with high detection in the cerebral cortex and lesser detection in the basal ganglia. GENE STRUCTURE Chen et al. (2011) determined that the PRRT2 gene contains 4 exons, the first of which is noncoding. MAPPING Chen et al. (2011) stated that the PRRT2 gene maps to chromosome 16p11.2. GENE FUNCTION In HEK293T cells and brain extracts from mice, Lee et al. (2012) demonstrated that the PRRT2 protein interacted with SNAP25 (600322), a synaptosomal membrane. After transfection of PRRT2 into rat hippocampal cells, PRRT2 was detected in thin axonal processes exiting from the neuron cell bodies. MOLECULAR GENETICS In affected members of 8 unrelated Han Chinese families with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Chen et al. (2011) identified 3 different heterozygous truncating mutations in the PRRT2 gene (614386.0001-614386.0003). The first mutation was found by exome sequencing of a large 4-generation family with 17 affected individuals. Expression of a truncated form of PRRT2 in COS-7 cells showed loss of membrane targeting and localization of the truncated protein in the cytoplasm, suggesting interruption of protein function. Using a combination of exome sequencing and linkage analysis in 2 large Han Chinese families with EKD1, Wang et al. (2011) independently and simultaneously identified 2 different heterozygous truncating mutations in the PRRT2 gene (649dupC; 614386.0001 and 614386.0009, respectively) that completely segregated with the phenotype in each family. Two patients in each family also had infantile convulsion and choreoathetosis syndrome (ICCA; 602066). Analysis of 3 additional Han Chinese families with EKD1 revealed that 2 carried the 649dupC mutation and 1 had a different PRRT2 mutation (614386.0010). Heron et al. (2012) identified heterozygous mutations in the PRRT2 gene (see, e.g., 614386.0001 and 614386.0004-614386.0006) in 14 (82%) 17 families with benign familial infantile seizures-2 (BFIS2; 605751), and in 5 (83%) of 6 families with familial infantile convulsions with paroxysmal choreoathetosis, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (EKD1), cooccur. The 649insC mutation (614386.0001) was the most common mutation, found in affected members of 12 families with BFIS2 and in 3 families with ICCA. Overall, the 649insC mutation was found in 15 (79%) of the 19 families with ICCA or BFIS2 studied. The families were of different ethnic origin, including Australasian of western European heritage, Swedish, and Israeli Sephardic-Jewish, and there was no evidence of a common haplotype among these families, indicating a mutation hotspot. These findings demonstrated that mutations in PRRT2 cause both epilepsy and a movement disorder, with obvious pleiotropy in age of expression. Lee et al. (2012) also identified heterozygous mutations in the PRRT2 gene (see, e.g., 614386.0007 and 614386.0008) in affected members of families with ICCA. The mutations were identified by whole-genome sequencing of 6 well-characterized families. The findings were confirmed by the identification of PRRT2 mutations in 24 of 25 additional families with the disorder. The 649insC mutation was the most common mutation. Sanger sequencing of a third cohort of 78 probands with a less clear clinical diagnosis found that 10 patients with familial disease and 17 with sporadic disease had the common 649insC mutation; 1 additional patient had a different truncating PRRT2 mutation. None of the pathogenic alleles were found in over 2,500 control chromosomes. There was intrafamilial variability of the phenotype. In vitro functional expression assays showed that the mutant truncating proteins were not expressed and did not exert dominant-negative effect on the wildtype protein, suggesting haploinsufficiency as the pathologic mechanism.
  • OMIM diseaseSee_Also:
  • OMIM diseaseAllelic_Variants: .0001 EPISODIC KINESIGENIC DYSKINESIA 1 CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS, INCLUDED;; SEIZURES, BENIGN FAMILIAL INFANTILE, 2, INCLUDED PRRT2, 1-BP DUP, 649C In affected members of 6 unrelated Han Chinese families with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Chen et al. (2011) identified a heterozygous 1-bp duplication (649dupC) in exon 2 of the PRRT2 gene in the proline-rich domain, resulting in a frameshift and introduction of a stop codon 7 amino acids downstream. The mutation was found by exome sequencing of a large 4-generation family with 17 affected individuals. The mutation completely segregated with the phenotype in each family and was not found in unaffected family members. The mutation was not found in 1,000 Han Chinese controls. Expression of a truncated form of PRRT2 in COS-7 cells showed loss of membrane targeting and localization of the truncated protein in the cytoplasm. A 189-kb common haplotype flanking the mutation was found in 3 of the families, a second different haplotype was found in 2 other families, and a third haplotype was found in the third family. Clinical features of the proband of 1 family was described in detail. He had onset at age 6 years of dystonic posturing of the head and arm, usually triggered by standing up quickly. This occurred up to 10 times per day, and lasted about 5 to 10 minutes. Brain MRI and EEG were normal at age 9 years. Treatment with carbamazepine resulted in complete symptom resolution. Using a combination of exome sequencing and linkage analysis in a large Han Chinese family with EKD1, Wang et al. (2011) independently and simultaneously identified a heterozygous 649dupC mutation in the PRRT2 gene that completely segregated with the phenotype. The mutation was predicted to result in a truncated protein containing only 223 amino acids and lacking the transmembrane segment. Two patients in the family also had infantile convulsion and choreoathetosis syndrome (ICCA; 602066). Analysis of 3 additional Chinese Han families with EKD1 revealed that 2 carried the 649dupC mutation. The mutation was not found in 500 controls. There was some phenotypic variability: the first family had dystonia, choreoathetosis or athetosis, the second family had predominant dystonia of the upper limbs, whereas the third had predominant dystonia of the lower limbs. In affected members of 3 unrelated families with familial infantile convulsions with paroxysmal choreoathetosis, Heron et al. (2012) identified a heterozygous 649insC mutation. This heterozygous mutation was also found in 12 unrelated families with benign familial infantile seizures-2 (BFIS2; 605751). Overall, the 649insC mutation was found in 15 (79%) of the 19 families with ICCA or BFIS2 studied. There was no evidence of a common haplotype among these families. The PRRT2 649insC mutation clearly occurs at a mutation hotspot, and occurs in a homopolymer of 9 C bases adjacent to 4 G bases. This DNA sequence has the potential to form a hairpin-loop structure, possibly leading to DNA-polymerase slippage and the insertion of an extra C base during DNA replication. .0002 EPISODIC KINESIGENIC DYSKINESIA 1 PRRT2, 4-BP DEL, 514TCTG In a Han Chinese mother and son with EKD1 (128200), Chen et al. (2011) identified a heterozygous 4-bp deletion (514delTCTG) in exon 2 of the PRRT2 gene in the proline-rich domain, resulting in a frameshift and premature truncation. The mutation was not found in 1,000 Han Chinese controls. Expression of a truncated form of PRRT2 in COS-7 cells showed loss of membrane targeting and localization of the truncated protein in the cytoplasm. .0003 EPISODIC KINESIGENIC DYSKINESIA 1 PRRT2, 1-BP DEL, 972A In a Han Chinese man with EKD1 (128200), Chen et al. (2011) identified a heterozygous 1-bp deletion (972delA) in exon 3 of the PRRT2 gene, resulting in a frameshift and premature truncation in the second transmembrane motif. The deceased father was reportedly affected, but DNA was not available. The mutation was not found in 1,000 Han Chinese controls. Expression of a truncated form of PRRT2 in COS-7 cells showed loss of membrane targeting and localization of the truncated protein in the cytoplasm. .0004 CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS PRRT2, 1-BP INS, 629C In affected members of a large multigenerational family with familial infantile convulsions with paroxysmal choreoathetosis (602066), Heron et al. (2012) identified a heterozygous 1-bp insertion (629insC) in the PRRT2 gene, resulting in a frameshift and premature truncation. There was intrafamilial variability of the phenotype. .0005 CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS PRRT2, SER317ASN In affected members of a large multigenerational family with ICCA (602066), Heron et al. (2012) identified a heterozygous 950G-A transition in the PRRT2 gene, resulting in a ser317-to-asn (S317N) substitution in a highly conserved residue. There was intrafamilial variability of the phenotype. .0006 SEIZURES, BENIGN FAMILIAL INFANTILE, 2 PRRT2, IVS2DS, G-A, +5 In affected members of a large family with benign familial infantile seizures-2 (BFIS2; 605751), Heron et al. (2012) identified a heterozygous G-to-A transition in intron 2 of the PRRT2 gene (879+5G-A), which reduces the splice site score. .0007 CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS PRRT2, ARG240TER In affected members of 2 families with ICCA (602066), Lee et al. (2012) identified a heterozygous C-to-T transition in the PRRT2 gene, resulting in an arg240-to-ter (R240X) substitution. There was intrafamilial variability of the phenotype. .0008 CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS PRRT2, 1-BP INS, 516T In affected members of a family with ICCA (602066), Lee et al. (2012) identified a heterozygous 1-bp insertion (516insT) in the PRRT2 gene, resulting in premature truncation at residue 173. There was intrafamilial variability of the phenotype. .0009 EPISODIC KINESIGENIC DYSKINESIA 1 CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS, INCLUDED PRRT2, GLN163TER Using a combination of exome sequencing and linkage analysis in a large Han Chinese family with EKD1 (128200), Wang et al. (2011) identified a heterozygous 487C-T transition in exon 2 of the PRRT2 gene that completely segregated with the phenotype. The mutation was predicted to result in a gln163-to-ter (Q163X) substitution and a truncated protein containing only 162 amino acids and lacking the transmembrane segment. Two patients in the family also had infantile convulsion and choreoathetosis syndrome (ICCA; 602066). The mutation was not found in 500 controls. .0010 EPISODIC KINESIGENIC DYSKINESIA 1 PRRT2, ARG266TRP In a Han Chinese mother and daughter with EKD1 (128200), Wang et al. (2011) identified a heterozygous 796C-T transition in exon 2 of the PRRT2 gene, resulting in an arg266-to-trp (R266W) substitution in a highly conserved residue. The mutation was not found in 500 controls.
  • OMIM diseaseCreation_Date: Patricia A. Hartz: 12/9/2011
  • OMIM diseaseEdit_History_Data: terry: 04/06/2012 carol: 4/6/2012 ckniffin: 4/5/2012 carol: 2/21/2012 ckniffin: 2/15/2012 carol: 12/12/2011 ckniffin: 12/12/2011 mgross: 12/9/2011
  • OMIM diseaseContributors: Cassandra L. Kniffin - updated: 4/5/2012 Cassandra L. Kniffin - updated: 2/15/2012 Cassandra L. Kniffin - updated: 12/12/2011
  • OMIM diseaseReference: 1. Chen, W.-J.; Lin, Y.; Xiong, Z.-Q.; Wei, W.; Ni, W.; Tan, G.-H.; Guo, S.-L.; He, J.; Chen, Y.-F.; Zhang, Q.-J.; Li, H.-F.; Lin, Y.; Murong, S.-X.; Xu, J.; Wang, N.; Wu, Z.-Y.: Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nature Genet. 43: 1252-1255, 2011. 2. Heron, S. E.; Grinton, B. E.; Kivity, S.; Afawi, Z.; Zuberi, S. M.; Hughes, J. N.; Pridmore, C.; Hodgson, B. L.; Iona, X.; Sadleir, L. G.; Pelekanos, J.; Herlenius, E.; and 12 others: PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am. J. Hum. Genet. 90: 152-160, 2012. 3. Lee, H.-Y.; Huang, Y.; Bruneau, N.; Roll, P.; Roberson, E. D. O.; Hermann, M.; Quinn, E.; Maas, J.; Edwards, R.; Ashizawa, T.; Baykan, B.; Bhatia, K.; and 29 others: Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep. 1: 2-12, 2012. 4. Wang, J.-L.; Cao, L.; Li, X.-H.; Hu, Z.-M.; Li, J.-D.; Zhang, J.-G.; Liang, Y.; San-A; Li, N.; Chen, S.-Q.; Guo, J.-F.; Jiang, H.; and 12 others: Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain 134: 3493-3501, 2011.