Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proline-rich transmembrane protein 2 (PRRT2), the causative gene of paroxysmal kinesigenic dyskinesias (PKD), benign familial infantile seizures (BFIS) and infantile convulsions with paroxysmal choreoathetosis (ICCA), also causes a variety of neurological paroxysmal disorders. These diseases share the same characteristics which may be due to the same genetic defect. We therefore propose to name them as PRRT2-related paroxysmal disorders (PRPDs) in order to assist clinical diagnosis, treatment and prognosis. This paper has reviewed the clinical phenotype, common features and pathogenesis of the PRPDs.
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PMID:[PRRT2 gene-related paroxysmal disorders]. 2529 89

See Lerche (doi:10.1093/brain/awy073) for a scientific commentary on this article.Proline-rich transmembrane protein 2 (PRRT2) is the causative gene for a heterogeneous group of familial paroxysmal neurological disorders that include seizures with onset in the first year of life (benign familial infantile seizures), paroxysmal kinesigenic dyskinesia or a combination of both. Most of the PRRT2 mutations are loss-of-function leading to haploinsufficiency and 80% of the patients carry the same frameshift mutation (c.649dupC; p.Arg217Profs*8), which leads to a premature stop codon. To model the disease and dissect the physiological role of PRRT2, we studied the phenotype of neurons differentiated from induced pluripotent stem cells from previously described heterozygous and homozygous siblings carrying the c.649dupC mutation. Single-cell patch-clamp experiments on induced pluripotent stem cell-derived neurons from homozygous patients showed increased Na+ currents that were fully rescued by expression of wild-type PRRT2. Closely similar electrophysiological features were observed in primary neurons obtained from the recently characterized PRRT2 knockout mouse. This phenotype was associated with an increased length of the axon initial segment and with markedly augmented spontaneous and evoked firing and bursting activities evaluated, at the network level, by multi-electrode array electrophysiology. Using HEK-293 cells stably expressing Nav channel subtypes, we demonstrated that the expression of PRRT2 decreases the membrane exposure and Na+ current of Nav1.2/Nav1.6, but not Nav1.1, channels. Moreover, PRRT2 directly interacted with Nav1.2/Nav1.6 channels and induced a negative shift in the voltage-dependence of inactivation and a slow-down in the recovery from inactivation. In addition, by co-immunoprecipitation assays, we showed that the PRRT2-Nav interaction also occurs in brain tissue. The study demonstrates that the lack of PRRT2 leads to a hyperactivity of voltage-dependent Na+ channels in homozygous PRRT2 knockout human and mouse neurons and that, in addition to the reported synaptic functions, PRRT2 is an important negative modulator of Nav1.2 and Nav1.6 channels. Given the predominant paroxysmal character of PRRT2-linked diseases, the disturbance in cellular excitability by lack of negative modulation of Na+ channels appears as the key pathogenetic mechanism.
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PMID:PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity. 2959 68

Benign familial infantile epilepsy (BFIE) is characterized by non-febrile focal seizures, which sometimes evolve to secondarily generalized seizures and are usually resolved in the second year. Proline-rich transmembrane protein 2 (PRRT2) is confirmed as the major cause of BFIE, familial paroxysmal kinesigeneic dystonia (PKD) and infantile convulsions and choreoathetosis (ICCA) syndrome. We examined a female patient with a hot spot mutation of PRRT2 gene. She had recurrent tonic seizures when she was three months old. The seizures were controlled by several kinds of anticonvulsants. Then, she had several times of focal seizures daily at nine months old. However, the seizures were stopped by small amounts of carbamazepine. Later, when she was two years old, she experienced frequent motor seizures characterized by truncal flexion and swaying the body with partially disturbed consciousness. Her father also had the same PRRT2 gene mutation and non-febrile seizures in infancy. The patient had mild to moderate mental retardation, whereas her father was mentally normal. Therefore, the patient revealed a quiet different phenotype from that of her father as a carrier of the same PRRT2 gene mutation. We speculate that the PRRT2 mutation had caused the BFIE-like seizures both in the patient and her father, whereas other unknown genetic factors specific for the patient might be associated with the atypical seizures observed only in her.
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PMID:A female patient with a hot spot mutation of PRRT2 gene suffering from several types of epileptic seizures in infancy. 3001 Feb 81

Proline-rich transmembrane protein 2 (PRRT2) was identified as the causative gene of paroxysmal kinesigenic choreoathetosis (PKC) as well as various other neurological diseases. However, the molecular mechanisms of how mutant PRRT2 leads to abnormal synaptic function and triggers PKC are still obscure. We generated a Prrt2 truncated mutant rat model which shows spontaneous PKC-like attacks with a relative low frequency as well as increased susceptibility to pentylenetetrazol (PTZ)-induced seizures. We demonstrate that PRRT2 is expressed on both pre- and post-synaptic membranes in the M1 cortex. PRRT2 negatively regulates SNARE complex assembly through interaction with SNAP25, STX1A, and VAMP2. In the M1 cortex of the rat model, release of amino acid neurotransmitters is increased. Protein levels of glutamate receptor subunit GRIA1 are significantly increased in PRRT2 mutant rats, while GABA receptor subunits GABRA1 are significantly reduced. Both frequency and amplitude of mEPSC are significantly increased, while amplitude of mIPSC is decreased and the ratio of mEPSC/mIPSC is significantly increased. The balance between excitatory and inhibitory neuronal activity is disrupted, which could lead to abnormal neuronal hyperexcitability. These results provide new insights into the function of PRRT2 in synaptic transmission and movement control, as well as the pathogenic mechanism underlying PKC.
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PMID:PRRT2 deficiency induces paroxysmal kinesigenic dyskinesia by influencing synaptic function in the primary motor cortex of rats. 3034 67