PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy.
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.


CONCLUSIONS
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.
Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia.
Michael S
MS
Hildebrand
Bioinformatics Division, The Walter and Eliza Hall Institute Melbourne, Victoria, Australia.
Rick
R
Tankard
The Florey Institute for Neuroscience and Mental Health, The University of Melbourne Melbourne, Victoria, Australia.
Elena V
EV
Gazina
Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia.
John A
JA
Damiano
Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia.
Kate M
KM
Lawrence
Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia.
Hans-Henrik M
HH
Dahl
Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia.
Brigid M
BM
Regan
Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics Iowa City, Iowa.
Aiden Eliot
AE
Shearer
Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics Iowa City, Iowa.
Richard J H
RJ
Smith
Pediatric Neurology and Neurogenetics Unit and Laboratories, A. Meyer Children's Hospital-University of Florence Florence, Italy.
Carla
C
Marini
Pediatric Neurology and Neurogenetics Unit and Laboratories, A. Meyer Children's Hospital-University of Florence Florence, Italy.
Renzo
R
Guerrini
Institute of Neurology, University Magna Græcia Catanzaro, Italy ; Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR) Germaneto, CZ, Italy.
Angelo
A
Labate
Institute of Neurology, University Magna Græcia Catanzaro, Italy ; Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR) Germaneto, CZ, Italy.
Antonio
A
Gambardella
Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi and Department of Medical and Surgical Sciences, University of Bologna Bologna, Italy.
Paolo
P
Tinuper
Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi and Department of Medical and Surgical Sciences, University of Bologna Bologna, Italy.
Laura
L
Lichetta
Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi and Department of Medical and Surgical Sciences, University of Bologna Bologna, Italy.
Sara
S
Baldassari
Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi and Department of Medical and Surgical Sciences, University of Bologna Bologna, Italy.
Francesca
F
Bisulli
Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi and Department of Medical and Surgical Sciences, University of Bologna Bologna, Italy.
Tommaso
T
Pippucci
Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia ; Department of Paediatrics, Royal Children's Hospital, University of Melbourne Melbourne, Victoria, Australia.
Ingrid E
IE
Scheffer
The Florey Institute for Neuroscience and Mental Health, The University of Melbourne Melbourne, Victoria, Australia.
Christopher A
CA
Reid
The Florey Institute for Neuroscience and Mental Health, The University of Melbourne Melbourne, Victoria, Australia.
Steven
S
Petrou
Bioinformatics Division, The Walter and Eliza Hall Institute Melbourne, Victoria, Australia.
Melanie
M
Bahlo
Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia.
Samuel F
SF
Berkovic
Autosomal recessive nocturnal frontal lobe epilepsy; PRIMA1; intellectual disability