Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy

Article Article scientifique Article Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy eng 2011-09-15 2012-01 author Salzmann Annick 0000-0003-0571-251X 510521 author Guipponi Michel 118157 author Lyons Peter J author Fricker Lloyd D author Sapio Matthew author Lambercy Carmen author Buresi Catherine 523272 author Ouled Amar Bencheikh Bouchra author Lahjouji Fatiha author Ouazzani Reda author Crespel Arielle author Chaigne Denys author Malafosse Alain 111681 124-135 10.1002/humu.21613 21922598 1059-7794 https://onlinelibrary.wiley.com/doi/10.1002/humu.21613 Febrile seizures (FS) and temporal lobe epilepsy (TLE) were found in four of the seven siblings born to healthy Moroccan consanguineous parents. We hypothesized autosomal recessive (AR) inheritance. Combined linkage analysis and autozygosity mapping of a genome-wide single nucleotide polymorphism genotyping identified a unique identical by descent (IBD) locus of 9.6 Mb on human chromosome 8q12.1-q13.2. Sequencing of the 38 genes mapped within the linked interval revealed a homozygous missense mutation c.809C>T (p.Ala270Val) in the carboxypeptidase A6 gene (CPA6). Screening all exons of CPA6 in unrelated patients with partial epilepsy (n = 195) and FS (n = 145) revealed a new heterozygous missense mutation c.799G>A (p.Gly267Arg) in three TLE patients. Structural modeling of CPA6 indicated that both mutations are located near the enzyme's active site. In contrast to wild-type CPA6, which is secreted and binds to the extracellular matrix where it is enzymatically active, Ala270Val CPA6 was secreted at about 40% of the level of the wild-type CPA6 and was fully active, while Gly267Arg CPA6 was not detected in the medium or extracellular matrix. This study suggests that CPA6 is genetically linked to an AR familial form of FS and TLE, and is associated with sporadic TLE cases. Adolescent Adult Carboxypeptidases A / genetics Carboxypeptidases A / metabolism Child Child, Preschool Chromosomes, Human, Pair 8 / genetics Chromosomes, Human, Pair 8 / metabolism Consanguinity DNA Mutational Analysis Epilepsies, Partial / complications Epilepsies, Partial / enzymology Epilepsies, Partial / genetics Epilepsy, Temporal Lobe / complications Epilepsy, Temporal Lobe / enzymology Epilepsy, Temporal Lobe / genetics Exons Female Genes, Recessive Genetic Linkage Genetic Loci Genome-Wide Association Study Genotype Homozygote Humans Infant Male Mutation, Missense Pedigree Polymorphism, Single Nucleotide Seizures, Febrile / complications Seizures, Febrile / enzymology Seizures, Febrile / genetics Dewey 616.89 Dewey 616 60 Département de psychiatrie 225 56 Département de médecine 221 false Human mutation 33 1 1691f348-417c-46cf-b452-9a9fc5b20262 Article (Published version) Restricted fb8e60_b53ea0abc9914cf484b8995b4392.pdf 648625 application/pdf f3614c35-a3c7-4e7a-a93c-81bc66d89475 Article (Accepted version) Public Salzmann_manuscripttext_Final.pdf 3255357 application/pdf dbd77519366eaeaa59fdbc41747d5e9a08554797c5c067f65e17a7d377ab9277 32fc9140-e394-433b-b461-019c95d523f1 Appendix Restricted humu_21613_sm_suppinfo.pdf 236143 application/pdf openAccess Faculté de médecine / Section de médecine clinique / Département de psychiatrie Faculté de médecine / Section de médecine clinique / Département de médecine

Title	Published in	Year	Views	Downloads

Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy	Human mutation	2012	247	1
GABA_B receptor 1 polymorphism (G1465A) and temporal lobe epilepsy	Epilepsia	2005	218	83

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Buresi, Catherine