PRIMA1 mutation: A new cause of nocturnal frontal lobe epilepsy

Michael S. Hildebrand, Rick Tankard, Elena V. Gazina, John A. Damiano, Kate M. Lawrence, Hans Henrik M Dahl, Brigid M. Regan, Aiden Eliot Shearer, Richard J H Smith, Carla Marini, Renzo Guerrini, Angelo Labate, Antonio Gambardella, Paolo Tinuper, Laura Lichetta, Sara Baldassari, Francesca Bisulli, Tommaso Pippucci, Ingrid E. Scheffer, Christopher A. ReidSteven Petrou, Melanie Bahlo, Samuel F. Berkovic

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)821-830
Number of pages10
JournalAnnals of Clinical and Translational Neurology
Volume2
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

Fingerprint

Frontal Lobe Epilepsy
Exome
Mutation
Acetylcholinesterase
Chromosomes, Human, Pair 14
Chromosomes, Human, Pair 8
Chromosomes, Human, Pair 7
Nicotinic Receptors
Cholinergic Receptors
Knockout Mice
Intellectual Disability
Synapses
Cholinergic Agents
Genes
Acetylcholine
Exons
Phenotype
Neurons
Messenger RNA

Keywords

  • PRIMA1
  • Autosomal recessive nocturnal frontal lobe epilepsy
  • Intellectual disability

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

Cite this

Hildebrand, M. S., Tankard, R., Gazina, E. V., Damiano, J. A., Lawrence, K. M., Dahl, H. H. M., ... Berkovic, S. F. (2015). PRIMA1 mutation: A new cause of nocturnal frontal lobe epilepsy. Annals of Clinical and Translational Neurology, 2(8), 821-830. https://doi.org/10.1002/acn3.224

PRIMA1 mutation : A new cause of nocturnal frontal lobe epilepsy. / 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.

In: Annals of Clinical and Translational Neurology, Vol. 2, No. 8, 01.08.2015, p. 821-830.

Research output: Contribution to journalArticle

Hildebrand, MS, Tankard, R, Gazina, EV, Damiano, JA, Lawrence, KM, Dahl, HHM, Regan, BM, Shearer, AE, Smith, RJH, Marini, C, Guerrini, R, Labate, A, Gambardella, A, Tinuper, P, Lichetta, L, Baldassari, S, Bisulli, F, Pippucci, T, Scheffer, IE, Reid, CA, Petrou, S, Bahlo, M & Berkovic, SF 2015, 'PRIMA1 mutation: A new cause of nocturnal frontal lobe epilepsy', Annals of Clinical and Translational Neurology, vol. 2, no. 8, pp. 821-830. https://doi.org/10.1002/acn3.224
Hildebrand MS, Tankard R, Gazina EV, Damiano JA, Lawrence KM, Dahl HHM et al. PRIMA1 mutation: A new cause of nocturnal frontal lobe epilepsy. Annals of Clinical and Translational Neurology. 2015 Aug 1;2(8):821-830. https://doi.org/10.1002/acn3.224
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. / PRIMA1 mutation : A new cause of nocturnal frontal lobe epilepsy. In: Annals of Clinical and Translational Neurology. 2015 ; Vol. 2, No. 8. pp. 821-830.
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AU - Lawrence, Kate M.

AU - Dahl, Hans Henrik M

AU - Regan, Brigid M.

AU - Shearer, Aiden Eliot

AU - Smith, Richard J H

AU - Marini, Carla

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AU - Labate, Angelo

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AU - Tinuper, Paolo

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AU - Pippucci, Tommaso

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