Mutation Analysis of MR-1, SLC2A1, and CLCN1 in 28 PRRT2-negative Paroxysmal Kinesigenic Dyskinesia Patients.
BACKGROUND
Paroxysmal kinesigenic dyskinesia (PKD) is the most common subtype of paroxysmal dyskinesias and is caused by mutations in PRRT2 gene. The majority of familial PKD was identified to harbor PRRT2 mutations. However, over two-third of sporadic PKD patients did not carry anyPRRT2 mutation, suggesting an existence of additional genetic mutations or possible misdiagnosis due to clinical overlap.


METHODS
A cohort of 28 Chinese patients clinically diagnosed with sporadic PKD and excluded PRRT2 mutations were recruited. Clinical features were evaluated, and all subjects were screened for MR-1, SLC2A1, and CLCN1 genes, which are the causative genes of paroxysmal nonkinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia, and myotonia congenita (MC), respectively. In addition, 200 genetically matched healthy individuals were recruited as controls.


RESULTS
A total of 16 genetic variants including 4 in MR-1 gene, 8 in SLC2A1 gene, and 4 in CLCN1 gene were detected. Among them, SLC2A1 c.363G>A mutation was detected in one case, and CLCN1 c.1205C>T mutation was detected in other two cases. Neither of them was found in 200 controls as well as 1000 Genomes database and ExAC database. Both mutations were predicted to be pathogenic by SIFT and PolyPhen2. The SLC2A1 c.363G>A mutation was novel.


CONCLUSIONS
The phenotypic overlap may lead to the difficulty in distinguishing PKD from PNKD and MC. For those PRRT2- negative PKD cases, screening of SLC2A1 and CLCN1 genes are useful in confirming the diagnosis.
Hong-Xia
HX
Wang
Hong-Fu
HF
Li
Gong-Lu
GL
Liu
Xiao-Dan
XD
Wen
Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040; Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, The Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
Zhi-Ying
ZY
Wu
D000293:Adolescent; D000328:Adult; D002648:Child; D018118:Chloride Channels / Q000235:genetics*; D002819:Chorea / Q000235:genetics; D004421:Dystonia / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D051272:Glucose Transporter Type 1 / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D009224:Myotonia Congenita / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*
C086321:CLC-1 channel; D018118:Chloride Channels; D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; C495444:PNKD protein, human; C569370:PRRT2 protein, human; C495677:SLC2A1 protein, human