Journal article
PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy
Annals of clinical and translational neurology, Vol.2(8), pp.821-830
08/2015
DOI: 10.1002/acn3.224
PMCID: PMC4554443
PMID: 26339676
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.
Details
- Title: Subtitle
- PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy
- Creators
- Michael S Hildebrand - University of MelbourneRick Tankard - The Walter and Eliza Hall InstituteElena V Gazina - The University of MelbourneJohn A Damiano - University of MelbourneKate M Lawrence - University of MelbourneHans‐Henrik M Dahl - University of MelbourneBrigid M Regan - University of MelbourneAiden Eliot Shearer - University of Iowa Hospitals and ClinicsRichard J. H Smith - University of Iowa Hospitals and ClinicsCarla Marini - A. Meyer Children's Hospital‐University of FlorenceRenzo Guerrini - A. Meyer Children's Hospital‐University of FlorenceAngelo Labate - Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM‐CNR)Antonio Gambardella - Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM‐CNR)Paolo Tinuper - University of BolognaLaura Lichetta - University of BolognaSara Baldassari - University of BolognaFrancesca Bisulli - University of BolognaTommaso Pippucci - University of BolognaIngrid E Scheffer - University of MelbourneChristopher A Reid - The University of MelbourneSteven Petrou - The University of MelbourneMelanie Bahlo - The Walter and Eliza Hall InstituteSamuel F Berkovic - University of Melbourne
- Resource Type
- Journal article
- Publication Details
- Annals of clinical and translational neurology, Vol.2(8), pp.821-830
- DOI
- 10.1002/acn3.224
- PMID
- 26339676
- PMCID
- PMC4554443
- NLM abbreviation
- Ann Clin Transl Neurol
- ISSN
- 2328-9503
- eISSN
- 2328-9503
- Number of pages
- 10
- Grant note
- National Health and Medical Research Council (NHMRC) (628952; 466671; 1006110; 1063799; APP1054618) Australian Government NHMRC IRIISS Telethon Foundation (GGP13200) Victorian State Government Operational Infrastructure Support Australian Research Council (ARC) (FT100100764)
- Language
- English
- Date published
- 08/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984006464102771
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