Role ofPRRT2in common paroxysmal neurological disorders: a gene with remarkable pleiotropy

Abstract

Mutations in the gene PRRT2 encoding proline-rich transmembrane protein 2 have recently been identified as the cause of three clinical entities: benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis (ICCA) syndrome, and paroxysmal kinesigenic dyskinesia (PKD). Patients with ICCA have both BFIE and PKD and families with ICCA may contain individuals who exhibit all three phenotypes. These three phenotypes were all mapped by linkage analyses to the pericentromeric region of chromosome 16, and were hypothesised to have the same genetic basis due to the co-occurrence of the disorders in some families. Despite considerable effort, the gene or genes for BFIE, ICCA, and PKD were not identified for many years after the linkage region was identified. Mutations in the gene PRRT2 were identified in several Chinese families with PKD, suggesting that the gene may also be responsible for ICCA and BFIE in families linked to the chromosome 16 locus. This was demonstrated to be the case, with the majority of families with ICCA and BFIE found to have PRRT2 mutations. The vast majority of these mutations are truncating and are predicted to lead to haploinsufficiency. PRRT2 is a largely uncharacterised protein. It is expressed in the brain and has been demonstrated to interact with SNAP-25, a component of the molecular machinery involved in the release of neurotransmitters at the presynaptic membrane. Therefore, the PRRT2 protein may play a role in this process. However, the molecular mechanisms underlying the remarkable pleiotropy associated with PRRT2 mutations have still to be determined.

Gene expression patterns in the hippocampus during the development and aging of Glud1(Glutamate Dehydrogenase 1) transgenic and wild type mice

“…Pex11b (peroxin 11b), a peroxisomal biogenesis factor, interacts with proteins involved in mitochondrial fission, is involved in lipid metabolism, myelin formation and axonal growth, and mutations in this and related Pex genes can lead to the inherited neurological and behavioral syndrome known as the Zellweger syndrome [47,48]. Prrt4 (proline-rich transmembrane protein 4), a gene related to Prrt2 , may be associated with abnormal neurological conditions as mutations in Prrt2 lead to paroxysmal neurological states characterized by seizures and dyskinesias [49]. Sfxn1 (sideroflexin 1) is a mitochondrial inner membrane tricarboxylate and iron carrier [50].…”

KCNT1mutations in seizure disorders: the phenotypic spectrum and functional effects

“…Several epilepsy genes are also associated with non-epileptic phenotypes. For example, mutations in PRRT2 can cause infantile epilepsy and/or paroxysmal movement disorders40 while mutations in TBC1D24 cause several forms of epilepsy and hearing loss as well as DOORS syndrome 41. In some cases, the pleiotropy results from the differing functional effects of particular mutations.…”

A novel topology of proline-rich transmembrane protein 2 (PRRT2): Hints for an intracellular function at the synapse.

“…A large number of PRRT2 nonsense, frameshift, and missense mutations have been associated with diseases with a variable phenotypic spectrum, ranging from mild forms that improve with age to severe phenotypes (1)(2)(3)(4)(5).…”