Disease relevance of PNKD

• BACKGROUND: Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder characterized by attacks of involuntary movements brought on by stress, alcohol, or caffeine, but not by movement [1].
• Paroxysmal dyskinesias (PxDs) are involuntary, episodic movements that include paroxysmal kinesigenic (PKD), paroxysmal nonkinesigenic (PNKD), and paroxysmal hypnogenic (PHD) varieties [2].
• We also review the cases of moyamoya-induced chorea reported previously, none of which resembled PKD or PNKD [3].
• The fact that three other paroxysmal neurological disorders (periodic ataxia with myokymia and hypo- and hyperkalemic periodic paralysis) are due to mutation in ion-channel genes raises the possibility that PDC is also due to an ion-channel gene mutation [4].
• Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) [5].

Psychiatry related information on PNKD

• Paroxysmal dystonic choreoathetosis (PDC) is characterized by attacks of involuntary movements that last up to several hours and occur at rest both spontaneously and following caffeine or alcohol consumption [4].
• Familial paroxysmal dystonic choreoathetosis (PDC) is an autosomal dominant neurological disorder characterized by episodes of involuntary movement precipitated by caffeine, alcohol, or emotional stress [6].

High impact information on PNKD

• Similarly, EAE was exacerbated in MR1-deficient mice, which lack V(alpha)19i T cells [7].
• T cells expressing an invariant V(alpha)19-J(alpha)33 T cell receptor alpha-chain (V(alpha)19i TCR) are restricted by the nonpolymorphic major histocompatibility complex class Ib molecule MR1 [7].
• Our results clearly establish the existence of a locus for autosomal dominant PDC on distal chromosome 2q [4].
• A gene for familial paroxysmal dyskinesia (FPD1) maps to chromosome 2q [8].
• We analyzed a Polish-American kindred with autosomal dominant PDC and identified tight linkage between the disorder and microsatellite markers on chromosome 2q (maximum two-point LOD score 4.77; recombination fraction 0) [4].

Chemical compound and disease context of PNKD

• The aim of this study was to describe the clinical features of a large Serbian family with paroxysmal nonkinesigenic dyskinesia (PNKD) and one of the two previously described mutations in the Myofibrillogenesis regulator 1 gene (MR-1), which causes an alanine-to-valine substitution at position 9 [9].
• It is similar in heme content and redox potential to the well known cytochromes c(3) but related in structure to the cytochrome c domain of soluble fumarate reductases from Shewanella sp. We report the crystal structure of the small tetraheme cytochrome c from Shewanella oneidensis MR-1 in two crystal forms and two redox states [10].
• L-glutamate per se was gliotoxic only at concentrations much higher than the maximum reached with the potent EAAT substrate inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (PDC), and toxicity was lower [11].
• Here we have demonstrated that a pure culture of Shewanella oneidensis strain MR-1 as well as enrichment cultures of Fe(III)-reducing bacteria from rice paddy soil and subsurface sediments are capable of conserving energy for growth with the structural Fe(III) bound in smectite clay as the sole electron acceptor [12].
• The aim of this study was to determine the apoptotic cell death in 92 thyroid carcinomas of different histotypes (42 papillary, PTC; 12 poorly differentiated, PDC: 21 undifferentiated, UC; and 17 medullary, MC) by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labelling (TUNEL) [13].

Biological context of PNKD

• We report mutations in the myofibrillogenesis regulator 1 (MR-1) gene causing PNKD in 50 individuals from eight families [14].
• Linkage of the disease to the PNKD, FHM, or ICCA loci was excluded as no common haplotype was shared by all the affected members for each locus [15].
• CONCLUSIONS: This family presented with the classic phenotype of PED and is not linked to the PNKD, FHM, or ICCA loci [15].
• Haplotypes were reconstructed for all the available family members by typing several microsatellite markers spanning the PNKD, FHM, and ICCA loci [15].
• RESULTS: Different missense mutations in exon 1 of MR1 that cosegregate with disease were identified in each multiplex family [1].

Anatomical context of PNKD

• The authors report the effect of chronic stimulation of the ventrointermediate (Vim) thalamus for treatment of dystonic paroxysmal nonkinesigenic dyskinesias (PNKD) [16].
• Northern blot revealed that the mRNA level of MR-1 was highest in the skeletal muscle and certain level of MR-1 expression was also observed in heart, liver and kidney [17].
• Immunohistochemical assay confirmed that the MR-1 protein existed in human myocardial myofibrils [17].
• These studies suggested that MR-1 might play a regulatory role in the muscle cell and it was worth investigating further [17].
• Selection and/or expansion of this population require B cells, and would involve a non-classical class I-related molecule MR1 [18].

Associations of PNKD with chemical compounds

• We have narrowed the disease interval to 4 cM and our findings provide support for the involvement of the gene for the chloride/bicarbonate exchanger as a candidate gene for PDC [19].
• The thymine and cytosine PNA monomers were used in conjunction with standard DNA synthesis monomers to produce chimeric PNA DNA (PDC) oligomers [20].
• We propose that nigrostriatal neurons in PDC patients have either marginally deficient dopamine synthesis or excessive alcohol- and caffeine-induced dopamine release; and that following alcohol- and caffeine-induced dopamine release, PDC patients experience a period of dopamine deficiency [21].
• Furthermore, the D439N mutation converted l-glutamate, THA, and PDC, which are activating substrates for the wild-type anion conductance, but not l-aspartate, into transient inhibitors of the EAAC1(D439) anion conductance [22].
• Moreover, high glutamate concentrations offered protection against PDC [11].

Other interactions of PNKD

• Paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by attacks of dystonia or chorea lasting minutes to hours [23].
• This study suggested that overexpression of MR-1 was associated with cancer cell proliferation and migration through MLC2 and that MR-1 might be a potential cancer therapeutic target [24].

Analytical, diagnostic and therapeutic context of PNKD

• These cases suggest that MMD should be included in the differential diagnosis of PKD and PNKD [3].
• The MR-1 gene was cloned from human skeletal muscle cDNA library by using a strategy that involves EST data base searching, PCR and RACE [17].
• We have taken advantage of our epitope-mapping studies of the E2 components of PDC, BCOADC, and OGDC, and constructed a "designer" hybrid clone, designated as pML-MIT3, that coexpresses the immunodominant epitopes within the three distinct lipoyl domains [25].
• Whilst in a model in which the regulation mechanism plays a critical role, e.g. donor-specific transfusion plus MR1-induced allograft tolerance, a deletional mechanism lowers the threshold for effective Treg action [26].
• For protracted treatment, we showed that readministration of recombinant adenovirus vectors could be facilitated by transient immunosuppression using a monoclonal antibody against CD40 ligand (MR1) [27].

References