HGNC Approved Gene Symbol: PRRT2
SNOMEDCT: 715534008;
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38) : 16:29,812,193-29,815,881 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p11.2 | Convulsions, familial infantile, with paroxysmal choreoathetosis | 602066 | Autosomal dominant | 3 |
| Episodic kinesigenic dyskinesia 1 | 128200 | Autosomal dominant | 3 | |
| Seizures, benign familial infantile, 2 | 605751 | Autosomal dominant | 3 |
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 expression in the cerebral cortex and lower expression in the basal ganglia.
Chen et al. (2011) determined that the PRRT2 gene contains 4 exons, the first of which is noncoding.
Chen et al. (2011) stated that the PRRT2 gene maps to chromosome 16p11.2.
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.
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 Q163X, 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%) of 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 649dupC 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 649dupC 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 649dupC 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 649dupC 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.
Meneret et al. (2012) identified heterozygous mutations in the PRRT2 gene (see, e.g., 614386.0001; 614386.0011-614386.0012) in 22 (65%) of 34 patients of European descent with EKD1 or ICCA. Mutations were found in 13 (93%) of 14 familial cases and in 9 (45%) of 20 sporadic cases. There was evidence for incomplete penetrance. The most common mutation was 649dupC, which was found in 17 of the 22 patients with PRRT2 mutations, although this was not due to a founder effect. Compared to patients without PRRT2 mutations, those with mutations had a slightly earlier age at onset (median age of 15 years and 9 years, respectively), but otherwise there were no phenotypic differences between the 2 groups. Most of the mutations caused premature termination, leading Meneret et al. (2012) to suggest that the disorders result from PRRT2 haploinsufficiency.
Schubert et al. (2012) identified a heterozygous 649dupC mutation in the PRRT2 gene in 39 of 49 families with BFIS2 and in 1 patient with sporadic occurrence of the disorder (77% of index cases). Three additional heterozygous PRRT2 mutations (see, e.g., 614386.0013; 614386.0014) were found in 3 other families with the disorder. The patients were of German, Italian, Japanese, and Turkish origin. Some of the families had previously been reported by Striano et al. (2006) and Weber et al. (2004). The 649dupC mutation, which occurs in an unstable DNA sequence of 9 cytosines, arose independently in families of different origin. Some unaffected family members also carried the mutation, indicating incomplete penetrance.
Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1, some of whom also had ICCA, and in 2 Japanese families with BFIS2. The mutation was shown to occur de novo in at least 1 family, suggesting that it is a mutation hotspot. EKD1, ICCA, and BFIS2 segregated with the mutation even within the same family. The findings indicated that all 3 disorders are allelic and are likely caused by a similar mechanism.
Heron and Dibbens (2013) reviewed the role of PRRT2 in 3 common neurologic disorders, EKD1, ICCA, and BFIS2, noting that there are no clear genotype/phenotype correlations.
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 of the insertion (Arg217ProfsTer8). 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 Han Chinese 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 649dupC mutation. This heterozygous mutation was also found in 12 unrelated families with benign familial infantile seizures-2 (BFIS2; 605751). Overall, the 649dupC 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 649dupC 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.
Meneret et al. (2012) found that the 649dupC mutation was the most common mutation in a cohort of patients of European descent with EKD1/ICCA. The mutation was present in 17 of 22 patients with PRRT2 mutations. Several unaffected family members also carried the mutation, indicating incomplete penetrance. There were at least 5 different haplotypes with the mutation, and it was found to occur de novo in 2 patients, indicating that it is a mutation hotspot.
Schubert et al. (2012) identified a heterozygous 649dupC mutation in the PRRT2 gene in 39 of 49 families with BFIS2 and in 1 patient with sporadic occurrence of the disorder (77% of index cases). The patients were of German, Italian, Japanese, and Turkish origin. The 649dupC mutation, which occurs in an unstable DNA sequence of 9 cytosines, arose independently in families of different origin. Some unaffected family members also carried the mutation, indicating incomplete penetrance.
Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1, some of whom also had ICCA, and in 2 Japanese families with BFIS2. The mutation was shown to occur de novo in at least 1 family, suggesting that it is a mutation hotspot. EKD1, ICCA, and BFIS2 segregated with the mutation even within the same family. The findings indicated that all 3 disorders are allelic and are likely caused by a similar mechanism.
In a Han Chinese mother and son with episodic kinesigenic dyskinesia-1 (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 termination. 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.
In a Han Chinese man with episodic kinesigenic dyskinesia-1 (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 termination 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.
In affected members of a large multigenerational family with familial infantile convulsions with paroxysmal choreoathetosis (ICCA; 602066), Heron et al. (2012) identified a heterozygous 1-bp insertion (629insC) in the PRRT2 gene, resulting in a frameshift and premature termination. There was intrafamilial variability of the phenotype.
In affected members of a large multigenerational family with familial infantile convulsions with paroxysmal choreoathetosis (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.
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.
In affected members of 2 families with familial infantile convulsions with paroxysmal choreoathetosis (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.
In affected members of a family with familial infantile convulsions with paroxysmal choreoathetosis (ICCA; 602066), Lee et al. (2012) identified a heterozygous 1-bp insertion (516insT) in the PRRT2 gene, resulting in premature termination at residue 173. There was intrafamilial variability of the phenotype.
Using a combination of exome sequencing and linkage analysis in a large Han Chinese family with episodic kinesigenic dyskinesia-1 (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.
In a Han Chinese mother and daughter with episodic kinesigenic dyskinesia-1 (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.
In 2 unrelated children of European descent with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Meneret et al. (2012) identified a heterozygous 1-bp deletion (649delC) in the PRRT2 gene, resulting in a frameshift and premature termination (Arg217GlufsTer12). This deletion occurred at the same nucleotide of a common duplication mutation (649dupC; 614386.0001), suggesting a mutation hotspot. One patient had a family history of the disorder. The other patient was thought to have sporadic disease, but the mutation was found in a parent, indicating incomplete penetrance.
In 3 affected individuals of a family of European descent with familial infantile convulsions with paroxysmal choreoathetosis (ICCA; 602066), Meneret et al. (2012) identified a heterozygous 562C-T transition in the PRRT2 gene, resulting in a gln188-to-ter (Q188X) substitution. The mutation was not found in 162 European control individuals.
In affected members of a large 2-generation German family (BFIS19) with benign familial infantile seizures-2 (BFIS2; 605751), Schubert et al. (2012) identified a heterozygous 1-bp deletion (629delC) in the PRRT2 gene, resulting in a frameshift and premature termination (Pro210GlnfsTer19).
In affected members of an Italian family (BFIS44) with benign familial infantile seizures-2 (BFIS2; 605751), Schubert et al. (2012) identified a heterozygous 1-bp deletion (291delC) in the PRRT2 gene, resulting in a frameshift and premature termination (Asn98ThrfsTer17).
In a Japanese woman with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Ono et al. (2012) identified a heterozygous 748C-T transition in the PRRT2 gene, resulting in a gln250-to-ter (Q250X) substitution in the N-terminal extracellular domain. Her daughter, who had benign familial infantile seizures-2 (BFIS2; 605751), also carried the mutation. The mutation was not found in 288 controls.
In 4 members of a large multigenerational Dutch family with benign familial infantile seizures-2 (BFIS2; 605751), Pelzer et al. (2014) identified a heterozygous 1-bp deletion (c.650delG) in the PRRT2 gene, resulting in a frameshift and premature termination (Arg217GlnfsTer12). Four family members without a history of febrile seizures also carried the mutation, indicating incomplete penetrance. The family had previously been reported by Terwindt et al. (1997) and Vanmolkot et al. (2003) as having both benign familial infantile seizures and familial hemiplegic migraine-2 (FHM2; 602481) associated with a heterozygous mutation in the ATP1A2 gene (R689Q; 182340.0004). Thus, 2 different neurologic disorders segregated in this family; the diagnosis was more complex as both disorders showed incomplete penetrance.
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Weber, Y. G., Berger, A., Bebek, N., Maier, S., Karafyllakes, S., Meyer, N., Fukuyama, Y., Halbach, A., Hikel, C., Kurlemann, G., Neubauer, B., Osawa, M., Pust, B., Rating, D., Saito, K., Stephani, U., Tauer, U., Lehmann-Horn, F., Jurkat-Rott, K., Lerche, H. Benign familial infantile convulsions: linkage to chromosome 16p12-q12 in 14 families. Epilepsia 45: 601-609, 2004. [PubMed: 15144424] [Full Text: https://doi.org/10.1111/j.0013-9580.2004.48203.x]