Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.
Hum Mutat
; 33(1): 124-35, 2012 Jan.
Article
en En
| MEDLINE
| ID: mdl-21922598
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Cromosomas Humanos Par 8
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Epilepsias Parciales
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Convulsiones Febriles
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Mutación Missense
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Carboxipeptidasas A
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Epilepsia del Lóbulo Temporal
Límite:
Adolescent
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Adult
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Hum Mutat
Asunto de la revista:
GENETICA MEDICA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Suiza