Functional study and pathogenicity classification of PRRT2 missense variants in PRRT2‐related disorders

Abstract

Aims PRRT2 variants are associated with various paroxysmal disorders. To date, more than 90 PRRT2 variants have been reported in PRRT2‐related disorders. Lack of functional study in majority of missense variants makes their pathogenicity uncertain. We aim to evaluate the clinical significance of PRRT2 missense variants by performing in vitro experiments.MethodsWe systematically reviewed PRRT2‐related disorders and summarized reported PRRT2 missense variants. Protein expression and subcellular localization of mutant PRRT2 were investigated in mammal cells. American College of Medical Genetics and Genomics (ACMG) guidelines were used to analyze the pathogenicity of PRRT2 missense variants.ResultsA total of 29 PRRT2 missense variants were identified in PRRT2‐related disorders. Ten variants were observed to affect both subcellular localization and protein level, three variants only affect membrane localization, and two variants only affect protein level. According to ACMG guidelines, 15 variants were finally classified as “likely pathogenic”, three as “benign”, three as “likely benign”, and eight as “uncertain significance” variants. The likely pathogenic variants were concentrated in the C‐terminal of PRRT2.ConclusionsThe pathogenicity of eight uncertain significance variants needs further investigation. C‐terminal of PRRT2 is crucial for its physiological function.

Clinical spectrum and genotype-phenotype correlations in PRRT2 Italian patients

“…Recently, childhood-onset epilepsy has been reported as part of the PRRT2 phenotypic spectrum [17]. In this study, we did also identify patients with unusual clinical features (i.e.…”

Clinical characteristics and genetics of ten Chinese children with PRRT2-associated neurological diseases

“…Six frameshift and 16 missense mutations were found in transmembrane domain 1 and 2 (TM1 and TM2), respectively, suggesting that the latter may play a more important role in the biological function of PRRT2. Zhao et al ( 23 ) studied the function and pathogenicity of PRRT2 missense variants in related diseases. Furthermore, 15 of the 29 PRRT2 missense variants were classified as likely pathogenic and were concentrated in the C-terminus, suggesting that the PRRT2 C-terminus is very important for its physiological function.…”

Proteomics‐based screening of the target proteins associated with antidepressant‐like effect and mechanism of Saikosaponin A

“…Proline‐rich transmembrane protein 2, enriched in cerebral cortex, cerebellum, substantia nigra and hippocampus, is an uncharacterized protein that belongs to the PRRT superfamily. It consists of four exons and encodes a 340‐amino‐acid protein with two predicted transmembrane (TM) domains in the C‐terminal and one proline‐rich domain in the N‐terminal . PRRT2 is involved in a group of paroxysmal disorders, such as epilepsy, paroxysmal kinesigenic dyskinesia(PKD) and migraine , but the PRRT2 function and pathogenic mechanisms remain largely obscure.…”

“…It consists of four exons and encodes a 340-amino-acid protein with two predicted transmembrane (TM) domains in the C-terminal and one proline-rich domain in the N-terminal. 41 PRRT2 is involved in a group of paroxysmal disorders, such as epilepsy, paroxysmal kinesigenic dyskinesia(PKD) and migraine 42,43 , but the PRRT2 function and pathogenic mechanisms remain largely obscure. A research published in Cell Research shows that PRRT2 is a presynaptic protein that interacts with components of the SNARE complex and down-regulates its formation, and mutations in PRRT2 would induce PKD-like phenotypes triggered by generalized seizures, hyperthermia or optogenetic stimulation of the cerebellum.…”