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 language | English |
|---|---|
| Pages (from-to) | 821-830 |
| Number of pages | 10 |
| Journal | Annals of Clinical and Translational Neurology |
| Volume | 2 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 1 2015 |
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Keywords
- PRIMA1
- Autosomal recessive nocturnal frontal lobe epilepsy
- Intellectual disability
ASJC Scopus subject areas
- Neuroscience(all)
- Clinical Neurology
Cite this
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 journal › Article
}
TY - JOUR
T1 - PRIMA1 mutation
T2 - A new cause of nocturnal frontal lobe epilepsy
AU - Hildebrand, Michael S.
AU - Tankard, Rick
AU - Gazina, Elena V.
AU - Damiano, John A.
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
AU - Guerrini, Renzo
AU - Labate, Angelo
AU - Gambardella, Antonio
AU - Tinuper, Paolo
AU - Lichetta, Laura
AU - Baldassari, Sara
AU - Bisulli, Francesca
AU - Pippucci, Tommaso
AU - Scheffer, Ingrid E.
AU - Reid, Christopher A.
AU - Petrou, Steven
AU - Bahlo, Melanie
AU - Berkovic, Samuel F.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - 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.
AB - 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.
KW - PRIMA1
KW - Autosomal recessive nocturnal frontal lobe epilepsy
KW - Intellectual disability
UR - http://www.scopus.com/inward/record.url?scp=84992268453&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84992268453&partnerID=8YFLogxK
U2 - 10.1002/acn3.224
DO - 10.1002/acn3.224
M3 - Article
VL - 2
SP - 821
EP - 830
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
SN - 2328-9503
IS - 8
ER -