The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway

Lee, Hsien-Yang; Xu, Ying; Huang, Yong; Ahn, Andrew H.; Auburger, Georg; Pandolfo, Massimo; Kwieciński, Hubert; Grimes, David A.; Lang, Anthony E.; Nielsen, Jørgen E.; Averyanov, Y.; Servidei, Serenella; Friedman, Andrzej; Bogaert, Patrick Van; Abramowicz, Marc; Bruno, Michiko Kimura; Sorensen, B.; Tang, Ling; Fu, Ying‐Hui; Ptáček, Louis J.

doi:10.1093/hmg/ddh330

Cited by 174 publications

(135 citation statements)

References 42 publications

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“…A Rabbit antibody (C2235) was raised against the carboxyl-terminus peptide of PNKD, and against the N-terminal peptide (2226) (9). RIM antibody (BD Biosciences) recognizes both RIM1 and RIM2.…”

Section: Methodsmentioning

confidence: 99%

“…PNKD is interesting in that the gene encodes a novel protein with homology to human glyoxalase II, an enzyme in a stress-response pathway. Although the normal role of PNKD is unknown, we previously identified the causative gene of PNKD (9) and a mouse model of the human mutations recapitulates the phenotype and shows dopamine signaling dysregulation (10).…”

mentioning

confidence: 99%

“…A previous investigation demonstrated specific expression of PNKD in neuronal subpopulations at the light microscopical level (9). We used immunogold electron microscopy to probe the ultrastructural localization of endogenous Pnkd in cortical tissue of adult mice, including the same region used for our initial pull-down experiments.…”

mentioning

confidence: 99%

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Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis

Shen¹,

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene but the function of the encoded protein remains unknown. We also generated a PNKD mouse model that revealed dysregulated dopamine signaling in vivo. Here, we show that PNKD interacts with synaptic active zone proteins Rab3-interacting molecule (RIM)1 and RIM2, localizes to synapses, and modulates neurotransmitter release. Overexpressed PNKD protein suppresses release, and mutant PNKD protein is less effective than wild-type at inhibiting exocytosis. In PNKD KO mice, RIM1/2 protein levels are reduced and synaptic strength is impaired. Thus, PNKD is a novel synaptic protein with a regulatory role in neurotransmitter release.paroxysmal dyskinesia | exocytosis | neurological disease P aroxysmal nonkinesigenic dyskinesia (PNKD)* is a rare dominantly inherited episodic movement disorder. First reported in 1940 (1), PNKD is characterized by childhood onset with involuntary movements in the limbs, trunk, and face manifesting as dystonia, chorea, and athetosis (2). PNKD shows nearly complete penetrance and attacks are precipitated by fatigue, stress, hunger, and consumption of coffee or alcohol. Patients are completely normal between attacks.Hereditary forms of many episodic disorders are recognized and include movement disorders, muscle diseases, cardiac arrhythmias, epilepsy, and headache. A majority of the causative genes that have been identified encode ion channels (3). Studies in several spontaneous mouse mutants with a paroxysmal dyskinesia phenotype have provided intriguing insights into these otherwise complicated diseases (4-6). The tottering and lethargic mice display motor abnormalities mimicking paroxysmal dyskinesia and harbor mutations in the genes encoding the α1A and β4 subunits of the P/Q-type voltage-gated Ca 2+ -channel, respectively (7,8). Like PNKD, the dyskinesia phenotype in tottering mice can also be triggered by caffeine and stress. PNKD is interesting in that the gene encodes a novel protein with homology to human glyoxalase II, an enzyme in a stress-response pathway. Although the normal role of PNKD is unknown, we previously identified the causative gene of PNKD (9) and a mouse model of the human mutations recapitulates the phenotype and shows dopamine signaling dysregulation (10).At synapses, vesicle priming, docking, and fusion at synaptic terminals are complex and coordinately regulated by proteins from the active zone, presynaptic membrane, and vesicles (11). Rab3-interacting molecules (RIMs) are a family of active zone proteins encoded by genes, Rims 1 to 4 (12). Through their interactions with vesicle proteins, active zone proteins, and presynaptic membrane proteins, RIMs are centrally involved in basic parameters of neurotransmitter release, and they contribute to both long-term and short-term synaptic plasticity (13-18).Given that PNKD is a novel protein whose function is unknown, we set out to identify ...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis

Shen¹,

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Although mutations in the MR1 gene located on chromosome 2q35 encoding a protein with unknown function have been described for PNKD (6,7), the underlying pathophysiology of PDs remains largely elusive. Analogous to idiopathic epilepsies and other episodic neurological disorders (8,9), disruption of ionic homeostasis by dysfunction of channels or transporters could play a pathophysiological role in PDs.…”

Section: Introductionmentioning

confidence: 99%

GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak

Weber¹,

Storch²,

Wuttke³

et al. 2008

J. Clin. Invest.

330

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Paroxysmal dyskinesias are episodic movement disorders that can be inherited or are sporadic in nature. The pathophysiology underlying these disorders remains largely unknown but may involve disrupted ion homeostasis due to defects in cell-surface channels or nutrient transporters. In this study, we describe a family with paroxysmal exertion-induced dyskinesia (PED) over 3 generations. Their PED was accompanied by epilepsy, mild developmental delay, reduced CSF glucose levels, hemolytic anemia with echinocytosis, and altered erythrocyte ion concentrations. Using a candidate gene approach, we identified a causative deletion of 4 highly conserved amino acids (Q282_S285del) in the pore region of the glucose transporter 1 (GLUT1). Functional studies in Xenopus oocytes and human erythrocytes revealed that this mutation decreased glucose transport and caused a cation leak that alters intracellular concentrations of sodium, potassium, and calcium. We screened 4 additional families, in which PED is combined with epilepsy, developmental delay, or migraine, but not with hemolysis or echinocytosis, and identified 2 additional GLUT1 mutations (A275T, G314S) that decreased glucose transport but did not affect cation permeability. Combining these data with brain imaging studies, we propose that the dyskinesias result from an exertion-induced energy deficit that may cause episodic dysfunction of the basal ganglia, and that the hemolysis with echinocytosis may result from alterations in intracellular electrolytes caused by a cation leak through mutant GLUT1.

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“…nausea, headache, diaphoresis, clumsiness, stiffening of the body, and dysarthric speech. The duration of the attacks is brief, lasting seconds to minutes, although prolonged attacks of 5-12 h have been described (Lee et al, 2004). Some individuals experience severe ataxia more than 15 times per day, whereas others experience attacks less than once a month (Van Dyke et al, 1975).…”

Section: Paroxysmal Movement Disordersmentioning

confidence: 99%

Animal Models of Episodic Ataxia Type 1 (EA1)

2015

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The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway

Cited by 174 publications

References 42 publications

Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis

Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis

GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak

Animal Models of Episodic Ataxia Type 1 (EA1)

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