Abstract
Paroxysmal kinesigenic dyskinesia (PKD) is characterized by recurrent and brief attacks of dystonia or chorea precipitated by sudden movements. It can be sporadic or familial. Proline-Rich Transmembrane Protein 2 (PRRT2) has been shown to be a common causative gene of PKD. However, less than 50% of patients with primary PKD harbor mutations in PRRT2. The aim of this study is to use eight families with PKD to identify the pathogenic PRRT2 mutations, or possible novel genetic cause of PKD phenotypes. After extensive clinical investigation, direct sequencing and mutation analysis of PRRT2 were performed on patients from eight PKD families. A genome-wide STR and SNP based linkage analysis was performed in one large family that is negative for pathogenic PRRT2 mutations. Using additional polymorphic markers, we identified a novel gene locus on chromosome 3q in this PRRT2-mutation-negative PKD family. The LOD score for the region between markers D3S1314 and D3S1256 is 3.02 and we proposed to designate this locus as Episodic Kinesigenic Dyskinesia (EKD3). Further studies are needed to identify the causative gene within this locus.
Highlights
Paroxysmal kinesigenic dyskinesia (PKD) is characterized by attacks of dystonia, chorea or athetosis lasting seconds to minutes
The second mutation, NM_001256442.1(PRRT2_v001):c.629dup [NM_001256442(PRRT2_i001):p.(Ala211Serfs*14)], was identified in family D. Both mutations have been previously reported in other ethnic groups and were predicted to result in mRNA degradation by non-sense mediated decay[15,16,17,18,19]
These findings suggest that Chinese PKD patients share common genetic characteristics with patients from other ethnic groups, which can be explained by the ancient founder-effect, or these loci might be mutation hotspots
Summary
Paroxysmal kinesigenic dyskinesia (PKD) is characterized by attacks of dystonia, chorea or athetosis lasting seconds to minutes. It can either be sporadic or familial. A potential relationship of PKD to epilepsy has been suggested, given the paroxysmal character, short duration of attacks, and co-occurrence of clinical diagnosis. Two partially overlapping PKD loci on chromosome 16, designated as Episodic Kinesigenic Dyskinesia 1 (EKD14; MIM #128200) and Episodic Kinesigenic Dyskinesia 2 (EKD25; MIM #611031), have been previously reported in familial PKD6–9. Proline-Rich Transmembrane Protein 2 (PRRT2) was considered as a PKD causative gene due to its overlapping location to EKD1/EKD2 region[5]. Less than 50% of patients with primary PKD10 have PRRT2 mutations. We sequenced PRRT2 in a cohort of eight independent Chinese PKD families and within one large PKD family negative for PRRT2 mutations (which was referred to as “Family A” below), we identified a novel PKD locus by linkage analysis, and we proposed to designate this novel PKD locus as Episodic Kinesigenic Dyskinesia 3 (EKD3)
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