LINKAGE ANALYSIS BETWEEN CHILDHOOD ABSENCE EPILEPSY AND [italic]GABRA5[/italic], [italic]GABRB3[/italic],and [italic]GABRG3[/italic] ON CHROMOSOME 15Q11-13
Abstract number :
3.084
Submission category :
Year :
2002
Submission ID :
1885
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Robert Robinson, Nichole Taske, Michelle Rees, Mark Gardiner. Paediatrics and Child Health, Royal Free and University College Medical School, University College London, London, United Kingdom
RATIONALE: Evidence suggests that mutations in genes encoding GABA[sub]A[/sub] receptor subunits may underlie childhood absence epilepsy (CAE). Linkage analysis in 33 nuclear families found weak evidence of linkage to the GABA[sub]A[/sub] receptor gene cluster on chromosome 15q11-13. The aim was to test this linkage in a larger collection of nuclear families each with two or more individuals with CAE.
METHODS: 74 families were ascertained from European populations. Individuals were classified as affected using diagnostic criteria based on the ILAE classification. Linkage to [italic]GABRB3[/italic], [italic]GABRA5[/italic], and [italic]GABRG3[/italic] on chromosome 15q11-13 was tested using three polymorphic microsatellite markers. Multipoint linkage analysis was carried out using GENEHUNTER.
RESULTS: Positive heterogeneity LOD scores were obtained for markers [italic]GABRB3CA, 155CA2, A55CA1[/italic] that encompass the GABA[sub]A[/sub] receptor subunit genes [italic]GABRB3[/italic], [italic]GABRA5[/italic], and [italic]GABRG3[/italic]. Assuming a recessive mode of inheritance, the maximum HLOD was 1.8 (alpha=0.37) at [italic]A55CA1[/italic], which lies between [italic]GABRA5[/italic] and [italic]GABRG3[/italic] and is approximately 20kb centromeric to [italic]GABRG3[/italic]. Assuming a dominant mode of inheritance, the maximum HLOD was 0.9 (alpha=0.29) at [italic]A55CA1[/italic]. The non-parametric linkage (NPL) score was 2.5 (p=0.004).
CONCLUSIONS: CAE shows a complex non-mendelian mode of inheritance. Both dominant and recessive susceptibility alleles may exist in several genes. These positive results are consistent with a contribution from [italic]GABRB3[/italic], [italic]GABRA5[/italic], or [italic]GABRG3[/italic] in a subset of patients. Further investigation of these genes is planned using both intrafamilial and case-control association analyses with intragenic single nucleotide polymorphisms (SNPs) in a larger number of patients.
[Supported by: Action Research
The Epilepsy Research Foundation
The Medical Research Foundation
The Wellcome Trust]