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

Hildebrand MS, Tankard R, Gazina EV, Damiano JA, Lawrence KM, Dahl HH, Regan BM, Shearer AE, Smith RJ, 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 - Ann Clin Transl Neurol (2015)

Bottom Line: No additional PRIMA1 mutations were found in 300 other NFLE cases.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.

View Article: PubMed Central - PubMed

Affiliation: Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

Pedigree of Australian family. Two-generation Australian family of Italian origin segregating ARNFLE (autosomal recessive nocturnal frontal lobe epilepsy) and intellectual disability showing genotypes of the PRIMA1 c.93+2 nucleotide. Open symbols unaffected; shaded symbols affected; double line consanguineous event; diagonal line deceased. A breast tissue sample was available from individual I:2 for genotyping by Sanger sequencing; blood samples were obtained from the other family members (I:1, II-1, II-2 and II-3), and these samples were exome sequenced.
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fig01: Pedigree of Australian family. Two-generation Australian family of Italian origin segregating ARNFLE (autosomal recessive nocturnal frontal lobe epilepsy) and intellectual disability showing genotypes of the PRIMA1 c.93+2 nucleotide. Open symbols unaffected; shaded symbols affected; double line consanguineous event; diagonal line deceased. A breast tissue sample was available from individual I:2 for genotyping by Sanger sequencing; blood samples were obtained from the other family members (I:1, II-1, II-2 and II-3), and these samples were exome sequenced.

Mentions: A two-generation Australian family of Italian origin with NFLE and intellectual disability was studied (Fig.1). The Human Research Ethics Committee of Austin Health, Melbourne, Australia, approved this study. Informed consent was obtained from living subjects or their relatives. For re-sequencing experiments, 300 sporadic patients diagnosed with NFLE were collected and phenotyped including 212 cases with Italian ancestry.


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

Hildebrand MS, Tankard R, Gazina EV, Damiano JA, Lawrence KM, Dahl HH, Regan BM, Shearer AE, Smith RJ, 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 - Ann Clin Transl Neurol (2015)

Pedigree of Australian family. Two-generation Australian family of Italian origin segregating ARNFLE (autosomal recessive nocturnal frontal lobe epilepsy) and intellectual disability showing genotypes of the PRIMA1 c.93+2 nucleotide. Open symbols unaffected; shaded symbols affected; double line consanguineous event; diagonal line deceased. A breast tissue sample was available from individual I:2 for genotyping by Sanger sequencing; blood samples were obtained from the other family members (I:1, II-1, II-2 and II-3), and these samples were exome sequenced.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554443&req=5

fig01: Pedigree of Australian family. Two-generation Australian family of Italian origin segregating ARNFLE (autosomal recessive nocturnal frontal lobe epilepsy) and intellectual disability showing genotypes of the PRIMA1 c.93+2 nucleotide. Open symbols unaffected; shaded symbols affected; double line consanguineous event; diagonal line deceased. A breast tissue sample was available from individual I:2 for genotyping by Sanger sequencing; blood samples were obtained from the other family members (I:1, II-1, II-2 and II-3), and these samples were exome sequenced.
Mentions: A two-generation Australian family of Italian origin with NFLE and intellectual disability was studied (Fig.1). The Human Research Ethics Committee of Austin Health, Melbourne, Australia, approved this study. Informed consent was obtained from living subjects or their relatives. For re-sequencing experiments, 300 sporadic patients diagnosed with NFLE were collected and phenotyped including 212 cases with Italian ancestry.

Bottom Line: No additional PRIMA1 mutations were found in 300 other NFLE cases.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.

View Article: PubMed Central - PubMed

Affiliation: Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia.

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.

No MeSH data available.


Related in: MedlinePlus