title: Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.
abstract: 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.
authors.affiliation: Department of Psychiatry, University of Geneva, Switzerland.
authors.forename: Annick
authors.initials: A
authors.lastname: Salzmann
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lyons
authors.forename: Lloyd D
authors.initials: LD
authors.lastname: Fricker
authors.forename: Matthew
authors.initials: M
authors.lastname: Sapio
authors.forename: Carmen
authors.initials: C
authors.lastname: Lambercy
authors.forename: Catherine
authors.initials: C
authors.lastname: Buresi
authors.forename: Bouchra
authors.initials: B
authors.lastname: Ouled Amar Bencheikh
authors.forename: Fatiha
authors.initials: F
authors.lastname: Lahjouji
authors.forename: Reda
authors.initials: R
authors.lastname: Ouazzani
authors.forename: Arielle
authors.initials: A
authors.lastname: Crespel
authors.forename: Denys
authors.initials: D
authors.lastname: Chaigne
authors.forename: Alain
authors.initials: A
authors.lastname: Malafosse
mesh_terms: D000293:Adolescent; D000328:Adult; D043422:Carboxypeptidases A / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics* / Q000378:metabolism; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004828:Epilepsies, Partial / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D005091:Exons; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D003294:Seizures, Febrile / Q000150:complications / Q000201:enzymology / Q000235:genetics*
chemical_list: D043422:Carboxypeptidases A