8.A.58.2.1
The proline-rich transmembrane protein of 340 aas, PRRT2 (Liu et al. 2016) belongs to the Dispanin (formerly the DUF4190) superfamily.  Mutations give rise to paroxysmal hypnogenic dyskinesia (PHD), which is considered to be a form of nocturnal frontal lobe epilepsy (NFLE) (Erro et al. 2017).  PRRT2 is the single causative gene for a group of paroxysmal syndromes of infancy, including epilepsy, paroxysmal movement disorders, and migraine (Robertson et al. 2019). Rossi et al. 2016 showed that PRRT2 is a type II transmembrane protein in which only the second hydrophobic segment spans the plasma membrane; the first one is associated with the internal surface of the membrane and forms a helix-loop-helix structure without crossing it. The large proline-rich N-terminal domain is localized intracellularly, and only the short C terminus is extracellular. PRRT2 interacts with the Src homology 3 domain-bearing protein, Intersectin 1, an intracellular protein involved in synaptic vesicle cycling. PRRT2 controls neuronal excitability by negatively modulating Na⁺ channel 1.2/1.6 activity (Fruscione et al. 2018). It interacts with several presynaptic proteins and voltage-gated Na⁺ channels. Several PRRT2 mutations are the main causes of a wide and heterogeneous spectrum of paroxysmal disorders with a loss-of-function pathomechanism as noted above. The highest expression levels of PRRT2 in brain occurs in cerebellar granule cells (GCs), and cerebellar dysfunctions participate in the dyskinetic phenotype of PRRT2 knockout (KO) mice. Binda et al. 2021 have investigated the effects of PRRT2 deficiency on the intrinsic excitability of GCs. They showed that PRRT2 KO primary GCs display increased expression of Na⁺ channels, increased amplitude of Na⁺ currents and increased length of the axon initial segment, leading to an overall enhancement of intrinsic excitability. In acute PRRT2 KO cerebellar slices, GCs were more prone to action potential discharge in response to mossy fiber activation and exhibited an enhancement of transient and persistent Na⁺ currents, in the absence of changes at the mossy fiber-GC synapses. Thus, a key role of PRRT2 expressed in GCs in the physiological regulation of the excitatory input to the cerebellum is consistent with a major role of a cerebellar dysfunction in the pathogenesis of the PRRT2-linked paroxysmal pathologies (Binda et al. 2021; Landolfi et al. 2021), especially paroxysmal kinesigenic dyskinesia (Ji et al. 2021). PRRT2 modulates presynaptic Ca²⁺ influx by interacting with P/Q-type channels (Ferrante et al. 2021). Self-limited familial infantile epilepsy (SFIE) is largely associated with variants in PRRT2, and antiepileptic drugs for SFIE have been discussed (Zhao et al. 2021). PRRT2 deficiency facilitates the induction of cerebellar spreading depolarization, and inhibition of cerebellar spreading depolarization prevents the occurrence of dyskinetic movements (Lu et al. 2021). SynDIG4 and PRRT1 act as typical AMPAR auxiliary proteins, while PRRT2 functions at presynaptic sites to regulate synaptic vesicle dynamics and is the causative gene for neurological paroxysmal disorders in humans (Dίaz 2021). PRRT2 specifically binds to GluA1 but has no effect on AMPA receptor-mediated synaptic transmission (Feng et al. 2022). For individuals with PRRT2-associated infantile epilepsy, sodium channel blockers are associated with reduced seizure frequency, but levetiracetam is not (Döring et al. 2022). PRRT2 is the single causative gene for pleiotropic paroxysmal syndromes including epilepsy, kinesigenic dyskinesia, episodic ataxia and migraine. PRRT2 is a neuron-specific type-2 membrane protein with a COOH-terminal intramembrane domain and a long proline-rich amino-terminal cytoplasmic region. PRRT2 is a neuron stability gene that negatively controls intrinsic excitability by regulating surface membrane localization and biophysical properties of voltage-dependent Na⁺ channels Nav1.2 and Nav1.6, but not Nav1.1. PRRT2 is a dual-domain protein in which the NH₂-terminal cytoplasmic region acts as a binding antenna for Na⁺ channels, while the COOH-terminal membrane domain regulates channel exposure on the membrane (Franchi et al. 2023). Missense mutations in the membrane domain of PRRT2 affect its interaction with Nav1.2 voltage-gated sodium channels (Sterlini et al. 2023).  Galcanezumab is a valid and well-tolerated treatment option in PRRT2-associated familial hemiplegic migraine (FHM) (Sottani et al. 2025).                                                                                                    .