PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy

Annals of Clinical and Translational Neurology
Michael S HildebrandSamuel F Berkovic

Abstract

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. Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. 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. 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 kn...Continue Reading

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Citations

May 22, 2016·Journal of Medical Genetics·Sara BaldassariTommaso Pippucci
Sep 17, 2019·International Journal of Cancer. Journal International Du Cancer·Claudio TomaSergi Castellví-Bel
Apr 10, 2016·Current Treatment Options in Neurology·Mar Carreño, Santiago Fernández
Jul 12, 2018·Clinical Genetics·K A MyersD A Dyment
Oct 16, 2018·Frontiers in Pharmacology·Jaya KumarSrijit Das
May 15, 2021·Sleep Medicine Clinics·Ting WuJerome Engel

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Methods Mentioned

BETA
exome sequencing
genotyping
PCR
electrophoresis
transfection

Software Mentioned

Analzyer Splice Site Tool
FEstim
GATK UnifiedGenotyper
LINKDATAGEN
GATK HaplotypeCaller
ANNOVAR
UCSC Genome Browser

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