PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy. Issue 8 (3rd July 2015)

• Record Type: Journal Article
• Authors: Hildebrand, Michael S.; Tankard, Rick; Gazina, Elena V.; Damiano, John A.; Lawrence, Kate M.; Dahl, Hans‐Henrik M.; Regan, Brigid M.; Shearer, Aiden Eliot; Smith, Richard J. H.; Marini, Carla; Guerrini, Renzo; Labate, Angelo; Gambardella, Antonio; Tinuper, Paolo; Lichetta, Laura; Baldassari, Sara; Bisulli, Francesca; Pippucci, Tommaso; Scheffer, Ingrid E.; Reid, Christopher A.; Petrou, Steven; Bahlo, Melanie; Berkovic, Samuel F.
• Is Part Of: Annals of clinical and translational neurology. Volume 2:Issue 8(2015:Aug.)
• Page Start: 821
• Page End: 830
• Publication Date: 2015-07-03
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.224
• Languages: English
• ISSNs: 2328-9503

Abstract

<abstract abstract-type="main" id="acn3224-abs-0001"> <title>Abstract</title> <sec id="acn3224-sec-0001" sec-type="section"> <title>Objective</title> <p>Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene.</p> </sec> <sec id="acn3224-sec-0002" sec-type="section"> <title>Methods</title> <p>Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation.</p> </sec> <sec id="acn3224-sec-0003" sec-type="section"> <title>Results</title> <p>Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the <italic>PRIMA1</italic> gene on chromosome 14. No additional <italic>PRIMA1</italic> mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the <italic>PRIMA1</italic> mRNA using a minigene system.</p> </sec> <sec id="acn3224-sec-0004" sec-type="section"> <title>Interpretation</title> <p>PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of <italic>PRIMA1</italic>. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first <italic>PRIMA1</italic> mutation implicated in disease.</p> </sec> </abstract>