Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia

Chen, Wan‐Jin; Lin, Ye; Xiong, Zhi‐Qi; Wei, Wei; Wang, Ni; Tan, Guangming; Guo, Shunling; He, J.; Chen, Ya-Fang; Zhang, Qijie; Li, Hongfu; Lin, Yi Wen; Murong, Shen-Xing; Xu, Jianfeng; Wang, Ning; Wu, Zhi‐Ying

doi:10.1038/ng.1008

Cited by 427 publications

(493 citation statements)

References 19 publications

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“…Sanger sequencing of PRRT2 revealed the recognized pathogenic (c.649_650InsC p.P217fsX7) heterozygous mutation [2][3][4][5][6][7] in all eight clinically affected individuals as well as in three of the seven clinically unaffected individuals (Fig. 1).…”

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confidence: 99%

“…Attacks usually respond to low-dose carbamazepine [1]. Mutations in PRRT2 have been identified as a cause of autosomal dominant PKD [2] and replicated in other studies [3][4][5][6][7]. It remains important to report the clinical characteristics of genetically defined families in order to fully describe the clinical syndrome, including the presence of additional associated features beyond the movement disorder.…”

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confidence: 99%

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Migraine with aura as the predominant phenotype in a family with a PRRT2 mutation

Sheerin¹,

Stamelou²,

Charlesworth³

et al. 2012

J Neurol

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confidence: 99%

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confidence: 99%

Migraine with aura as the predominant phenotype in a family with a PRRT2 mutation

Sheerin¹,

Stamelou²,

Charlesworth³

et al. 2012

J Neurol

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“…A detailed analysis of the primary structure of human PRRT2 identified the two predicted transmembrane helices in the C-terminal region of the protein (TM1, 3 amino acids 275-295; TM2, amino acids 324 -344): a long and relatively unstructured N-terminal region (amino acids 1-274), including a proline-rich domain (amino acids 133-222); an intracellular loop (amino acids 296 -323) connecting the two transmembrane helices; and a very short C-terminal end (8). The mouse PRRT2 ortholog is virtually identical to the human protein in the C terminus, with few differences in the N-terminal region (6).…”

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confidence: 99%

A novel topology of proline-rich transmembrane protein 2 (PRRT2): Hints for an intracellular function at the synapse.

Rossi¹,

Sterlini²,

Castroflorio³

et al. 2018

Journal of Biological Chemistry

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Proline-rich transmembrane protein 2 (PRRT2) has been identified as the single causative gene for a group of paroxysmal syndromes of infancy, including epilepsy, paroxysmal movement disorders, and migraine. On the basis of topology predictions, PRRT2 has been assigned to the recently characterized family of Dispanins, whose members share the two-transmembrane domain topology with a large N terminus and short C terminus oriented toward the outside of the cell. Because PRRT2 plays a role at the synapse, it is important to confirm the exact orientation of its N and C termini with respect to the plasma membrane to get clues regarding its possible function. Using a combination of different experimental approaches, including live immunolabeling, immunogold electron microscopy, surface biotinylation and computational modeling, we demonstrate a novel topology for this protein. PRRT2 is a type II transmembrane protein in which only the second hydrophobic segment spans the plasma membrane, whereas the first one is associated with the internal surface of the membrane and forms a helix-loop-helix structure without crossing it. Most importantly, the large proline-rich N-terminal domain is not exposed to the extracellular space but is localized intracellularly, and only the short C terminus is extracellular (N cyt /C exo topology). Accordingly, we show that PRRT2 interacts with the Src homology 3 domain-bearing protein Intersectin 1, an intracellular protein involved in synaptic vesicle cycling. These findings will contribute to the clarification of the role of PRRT2 at the synapse and the understanding of pathogenic mechanisms on the basis of PRRT2-related neurological disorders.Proline-rich transmembrane protein 2 (PRRT2) is encoded by a gene that has been shown recently to be the single causative gene for a group of paroxysmal syndromes of infancy, including benign familial infantile seizures, infantile convulsion choreoathetosis, migraine, hemiplegic migraine, and paroxysmal kinesigenic dyskinesia/choreoathetosis. A large number of PRRT2 nonsense, frameshift, and missense mutations have been associated with diseases with a variable phenotypic spectrum, ranging from mild forms that improve with age to severe phenotypes (1-5).The PRRT2 gene encodes for a protein highly conserved across species, with an average of 80% similarity across mammals and 30% with zebrafish. The sequence similarity increases in the C-terminal region containing the predicted transmembrane domains, becoming over 90% in mammals and 60% in zebrafish (6). On the basis of topology prediction, PRRT2 has been assigned to the newly characterized large family of Dispanins, whose members share the two-transmembrane domain topology and include the subfamily of interferon-induced transmembrane proteins.The putative topology of the Dispanins has been described as two transmembrane helices in the C-terminal region, separated by an intracellular loop of variable length, and an often long N-terminal region (Ͼ100 amino acids) compared with a short C-terminal region (...

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“…It has been demonstrated to be associated with mutations in several genes, including PRRT2 (proline‐rich region transmembrane protein‐2) (Chen et al, 2011), SLC2A1 (solute carrier family 2, member 1), MR‐1 (myofibrillogenesis regulator 1), CLCN1 (chloride voltage‐gated channel 1) (Wang, Li, Liu, Wen, & Wu, 2016), SCN8A (sodium voltage‐gated channel alpha subunit 8) (Chen et al, 2015), and ADCY5 (adenylyl cyclase 5) (Gardella et al, 2016). PRRT2 is the most common known causative gene for PKD.…”

Section: Introductionmentioning

confidence: 99%

16p11.2 deletion in patients with paroxysmal kinesigenic dyskinesia but without intellectual disability

Wang

et al. 2018

Brain and Behavior

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IntroductionMutations of the PRRT2 gene are the most common cause for paroxysmal kinesigenic dyskinesia. However, patients with negative PRRT2 mutations are not rare. The aim of this study is to determine whether copy number variant of PRRT2 gene is another potential pathogenic mechanism in the patients with paroxysmal kinesigenic dyskinesia with negative PRRT2 point and frameshift mutations.MethodsWe screened PRRT2 copy number variants using the AccuCopy™ method in 29 patients with paroxysmal kinesigenic dyskinesia with negative PRRT2 point and frameshift mutations. Next‐generation sequencing was used to determine the chromosomal deletion sites in patients with PRRT2 copy number variants, and to exclude mutations in other known causative genes for paroxysmal kinesigenic dyskinesia.ResultsTwo sporadic patients with negative PRRT2 point and frameshift mutations (6.9%) were identified to have de novo PRRT2 copy number deletions (591 and 832 Kb deletions located in 16p11.2). The two patients presented with pure paroxysmal kinesigenic dyskinesia and paroxysmal kinesigenic dyskinesia and benign infantile convulsions, respectively. They had normal intelligence and neuropsychiatric development, in contrast to those previously reported with 16p11.2 deletions complicated with neuropsychiatric disorders. No correlation between the deletion ranges and phenotypic variations was found.Conclusion16p11.2 deletions play causative roles in paroxysmal kinesigenic dyskinesia, especially for sporadic cases. Our findings extend the phenotype of 16p11.2 deletions to pure paroxysmal kinesigenic dyskinesia. Screening for 16p11.2 deletions should thus be included in genetic evaluations for patients with paroxysmal kinesigenic dyskinesia.

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Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia

Cited by 427 publications

References 19 publications

Migraine with aura as the predominant phenotype in a family with a PRRT2 mutation

Migraine with aura as the predominant phenotype in a family with a PRRT2 mutation

A novel topology of proline-rich transmembrane protein 2 (PRRT2): Hints for an intracellular function at the synapse.

16p11.2 deletion in patients with paroxysmal kinesigenic dyskinesia but without intellectual disability

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