PRIMA1, the proline rich membrane anchor 1 gene, encodes a transmembrane protein that anchors acetylcholinesterase (AChE) to membrane rafts of neurons. AChE hydrolyzes acetylcholine, and thus PRIMA1 is involved in cholinergic regulation, which is crucial for normal neuronal function [1].

A novel splice site mutation (c.93+2T>C) in PRIMA1 was identified in a family with autosomal recessive nocturnal frontal lobe epilepsy (NFLE). This mutation led to the skipping of the first coding exon of PRIMA1 mRNA, effectively knocking out PRIMA1 function. PRiMA knockout mice showed reduction of AChE and accumulation of acetylcholine at the synapse. These findings suggest that in this family, the loss-of-function mutation in PRIMA1 leads to enhanced cholinergic responses, causing severe NFLE and intellectual disability [1].

In conclusion, PRIMA1 is essential for normal cholinergic function at the neuronal synapse through its role in anchoring AChE. The study of PRIMA1 knockout mouse models, along with human genetic studies, has revealed its significance in the pathogenesis of nocturnal frontal lobe epilepsy, highlighting its potential as a therapeutic target for this disease.

References:

1. Hildebrand, Michael S, Tankard, Rick, Gazina, Elena V, Bahlo, Melanie, Berkovic, Samuel F. 2015. PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy. In Annals of clinical and translational neurology, 2, 821-30. doi:10.1002/acn3.224. https://pubmed.ncbi.nlm.nih.gov/26339676/