TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large‐Sample Study

Abstract

Background Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one‐third of PKD patients are attributed to proline‐rich transmembrane protein 2 (PRRT2) mutations. Objective We aimed to explore the potential causative gene for PKD. Methods A cohort of 196 PRRT2‐negative PKD probands were enrolled for whole‐exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case–control analysis, was applied to identify the candidate genes. Another 325 PRRT2‐negative PKD probands were subsequently screened with Sanger sequencing. Results Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A‐related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A‐positive and PRRT2‐positive groups. Conclusions We consolidated mutations in TMEM151A causing PKD with the aid of case–control analysis of a large‐scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A‐related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A‐related PKD. © 2021 International Parkinson and Movement Disorder Society

De Novo Mutation in TMEM151A and Paroxysmal Kinesigenic Dyskinesia

“…7 No other de novo class IV or V variant was identified in this cohort. The TMEM151A mutation was identified in one of 23 patients of our PRRT2negative PKD cohort, which is in accordance with the frequency of 4.8% found by Tian et al 1 We report on a de novo mutation in TMEM151A in a patient with PKD. Our findings confirm TMEM151A variants as a genetic cause of PKD and suggest that de novo mutations in this gene are infrequently responsible for ---------------------------------------------------------------------------------------------------------------------- sporadic PKD cases.…”

“…We read with great interest the article by Tian and colleagues. 1 Heterozygous mutations in TMEM151A, encoding transmembrane protein 151 A, a protein of undetermined function, have been very recently associated with paroxysmal kinesigenic dyskinesia (PKD) in the Chinese population. [1][2][3][4] TMEM151A is highly expressed in the brain, including the cerebral cortex and the thalamus and is highly conserved among species.…”

“…1 Heterozygous mutations in TMEM151A, encoding transmembrane protein 151 A, a protein of undetermined function, have been very recently associated with paroxysmal kinesigenic dyskinesia (PKD) in the Chinese population. [1][2][3][4] TMEM151A is highly expressed in the brain, including the cerebral cortex and the thalamus and is highly conserved among species. To definitively confirm the association between TMEM151A and PKD, other mutations in the same gene should be identified in independent cohorts from different populations.…”

Exome‐Wide Analyses in Paroxysmal Kinesigenic Dyskinesia Confirm TMEM151A as a Novel Causative Gene

“…To date, TMEM151A mutations have been reported in 52 PKD patients (including our cohort). 4,5 No obvious genotype-phenotype correlation was observed. Interestingly, all studies showed a high frequency of mutations in sporadic cases.…”

“…3 The lack of known inheritance could be partially attributable to the incomplete penetrance, which has been observed in TMEM151A variants very recently. 4,5 These complex genetic conditions limit the utility of traditional genetic segregation analysis. To date, the roles of genes operating via dominant transmission in PRRT2negative PKD patients have not been systematically studied.…”