Loss of the potassium channel beta-subunit gene, KCNAB2, is associated with epilepsy in patients with 1p36 deletion syndrome.
OBJECTIVE
Clinical features associated with chromosome 1p36 deletion include characteristic craniofacial abnormalities, mental retardation, and epilepsy. The presence and severity of specific phenotypic features are likely to be correlated with loss of a distinct complement of genes in each patient. We hypothesize that hemizygous deletion of one, or a few, critical gene(s) controlling neuronal excitability is associated with the epilepsy phenotype. Because ion channels are important determinants of seizure susceptibility and the voltage-gated K(+) channel beta-subunit gene, KCNAB2, has been localized to 1p36, we propose that deletion of this gene may be associated with the epilepsy phenotype.


METHODS
Twenty-four patients were evaluated by fluorescence in situ hybridization with a probe containing KCNAB2. Clinical details were obtained by neurologic examination and EEG.


RESULTS
Nine patients are deleted for the KCNAB2 locus, and eight (89%) of these have epilepsy or epileptiform activity on EEG. The majority of patients have a severe seizure phenotype, including infantile spasms. In contrast, of those not deleted for KCNAB2, only 27% have chronic seizures, and none had infantile spasms.


CONCLUSIONS
Lack of the beta subunit would be predicted to reduce K(+) channel-mediated membrane repolarization and increase neuronal excitability, suggesting a possible relation between loss of this gene and the development of seizures. Because some patients with seizures were not deleted for KCNAB2, there may be additional genes within 1p36 that contribute to epilepsy in this syndrome. Hemizygosity of this gene in a majority of monosomy 1p36 syndrome patients with epilepsy suggests that haploinsufficiency for KCNAB2 is a significant risk factor for epilepsy.
Heilstedt
H A
HA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Burgess
D L
DL
Anderson
A E
AE
Chedrawi
A
A
Tharp
B
B
Lee
O
O
Kashork
C D
CD
Starkey
D E
DE
Wu
Y Q
YQ
Noebels
J L
JL
Shaffer
L G
LG
Shapira
S K
SK
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000453:epidemiology / Q000235:genetics; D004569:Electroencephalography; D004827:Epilepsy / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008607:Intellectual Disability / Q000453:epidemiology / Q000235:genetics; D009154:Mutation / Q000235:genetics; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated