Loss of the Potassium Channel β‐Subunit Gene, KCNAB2, Is Associated with Epilepsy in Patients with 1p36 Deletion Syndrome

Abstract

Summary:Purpose: 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 ␤-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 ␤ 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.

Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma

“…KCNAB2 is a member of the shaker subfamily of voltage-gated potassium channels and serves an auxiliary role to the functional a subunit of the channel (McCormack et al, 2002). Our analysis found this gene to be preferentially expressed in brain, which is consistent with previous findings indicating an association between deletion of KCNAB2 and an epileptic phenotype in patients with monosomy 1p36.3 (Heilstedt et al, 2001). Finally, the transcription factor HKR3 and the death domain receptor TNFRSF25 have previously been identified and extensively evaluated as candidate neuroblastoma tumor suppressor genes Grenet et al, 1998), but no evidence to date implicates either in tumorigenesis.…”

A girl with 1p36 deletion syndrome and congenital fiber type disproportion myopathy

“…Phenotype/ genotype correlation and refinements of critical regions delineated specific areas for the causative genes (Wu et al 1999). For example, hemizygosity of KCNAB2 is a significant risk factor for severe epilepsy (Heilstedt et al 2001). Myopathy in our patient may be explained by haploinsufficiency of the putative causative genes or unmasking of certain recessive alleles.…”

Functional Coupling between the Kv1.1 Channel and Aldoketoreductase Kvβ1

“…In the central nervous system, Kv1 family channels are preferentially targeted to axons (31) and likely play an important role in controlling the invasion and propagation of an action potential. In humans, mutations of the Kv1 channel have been linked to episodic ataxia (32), and loss of the Kv␤ gene has been associated with seizures (33). In non-excitable T-lymphocytes, the activity of Kv1 channels changes significantly during the T-cell maturation process (34).…”