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    PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy

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    Author
    Hildebrand, MS; Tankard, R; Gazina, EV; Damiano, JA; Lawrence, KM; Dahl, H-HM; Regan, BM; Shearer, AE; Smith, RJH; Marini, C; ...
    Date
    2015-08-01
    Source Title
    Annals of Clinical and Translational Neurology
    Publisher
    WILEY
    University of Melbourne Author/s
    Damiano, John; Regan, Brigid; Berkovic, Samuel; Hildebrand, Michael; Esnault, Kate; DAHL, HANS-HENRIK; Scheffer, Ingrid; Gazina, Elena; Reid, Christopher; Petrou, Steven; ...
    Affiliation
    Florey Department of Neuroscience and Mental Health
    Medicine and Radiology
    School of Mathematics and Statistics
    Metadata
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    Document Type
    Journal Article
    Citations
    Hildebrand, M. S., Tankard, R., Gazina, E. V., Damiano, J. A., Lawrence, K. M., Dahl, H. -H. M., Regan, B. M., Shearer, A. E., Smith, R. J. H., Marini, C., Guerrini, R., Labate, A., Gambardella, A., Tinuper, P., Lichetta, L., Baldassari, S., Bisulli, F., Pippucci, T., Scheffer, I. E. ,... Berkovic, S. F. (2015). PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy. ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, 2 (8), pp.821-830. https://doi.org/10.1002/acn3.224.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257711
    DOI
    10.1002/acn3.224
    Abstract
    OBJECTIVE: 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. METHODS: Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. RESULTS: 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 PRIMA1 gene on chromosome 14. No additional PRIMA1 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 PRIMA1 mRNA using a minigene system. INTERPRETATION: 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 PRIMA1. 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 PRIMA1 mutation implicated in disease.

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