Truncation of the Shaker‐like voltage‐gated potassium channel, Kv1.1, causes megencephaly

Abstract

The megencephaly mouse, mceph/mceph, displays dramatically increased brain volume and hypertrophic brain cells. Despite overall enlargement, the mceph/mceph brain appears structurally normal, without oedema, hydrocephaly or leukodystrophy, and with only minor astrocytosis. Furthermore, it presents striking disturbances in expression of trophic and neuromodulating factors within the hippocampus and cortex. Using a positional cloning approach we have identified the mceph mutation. We show that mceph/mceph mice carry an 11-base-pair deletion in the gene encoding the Shaker-like voltage-gated potassium channel subtype 1, Kcna1. The mutation leads to a frame shift and the predicted MCEPH protein is truncated at amino acid 230 (out of 495), terminating with six aberrant amino acids. The expression of Kcna1 mRNA is increased in the mceph/mceph brain. However, the C-terminal domains of the corresponding Kv1.1 protein are absent. The putative MCEPH protein retains only the N-terminal domains for channel assembly and may congregate nonfunctional complexes of multiple Shaker-like subunits. Indeed, whereas Kcna2 and Kcna3 mRNA expression is normal, the mceph/mceph hippocampus displays decreased amounts of Kv1.2 and Kv1.3 proteins, suggesting interactions at the protein level. We show that mceph/mceph mice have disturbed brain electrophysiology and experience recurrent behavioural seizures, in agreement with the abnormal electrical brain activity found in Shaker mutants. However, in contrast to the commonly demonstrated epilepsy-induced neurodegeneration, we find that the mceph mutation leads to seizures with a concomitant increase in brain size, without overt neural atrophy.

Characterization of AtALMT1 Expression in Aluminum-Inducible Malate Release and Its Role for Rhizotoxic Stress Tolerance in Arabidopsis

“…The Shaker-type K 1 channel forms a tetrameric transporter complex where each protein subunit has five transmembrane domains similar to that seen with AtALMT1 (Yellen, 2002). In mouse, the mceph mutation leads to megencephaly and occurs at the Kv1.1 locus, which is an isoform of a Shaker-type K 1 channel (Petersson et al, 2003). Like AtALMT1-Wa-1, the mceph variant of Kv1.1 has a premature stop codon after the second transmembrane-spanning domain, which leads to heteromeric channel complexes with significantly altered K 1 transport functionality (Petersson et al, 2003).…”

“…In mouse, the mceph mutation leads to megencephaly and occurs at the Kv1.1 locus, which is an isoform of a Shaker-type K 1 channel (Petersson et al, 2003). Like AtALMT1-Wa-1, the mceph variant of Kv1.1 has a premature stop codon after the second transmembrane-spanning domain, which leads to heteromeric channel complexes with significantly altered K 1 transport functionality (Petersson et al, 2003). Genetic experiments with a T-DNA insertion allele of AtALMT1 (a null) and the Ler ecotype indicate a single copy of AtALMT1 can drive wild-type malate release rates (Hoekenga et al, 2006).…”

Animal Models of Episodic Ataxia Type 1 (EA1)

“…The expression of the remaining N-terminal domain, first TM, and extracellular loop may be responsible for the decreased amounts of Kv1.2 and Kv1.3 proteins that were detected in the hippocampus of mceph/mceph mice. Electrophysiological investigations from mceph/ mceph brain slices revealed hippocampal hyperexcitability consistent with limbic status epilepticus (Petersson et al, 2003). Interestingly, a mutation that results in truncation of the C-terminal domain of Kv1.1 channels (R417stop) has also been found in an EA1 proband displaying episodes of ataxia precipitated by exercise, stress, startle, and high temperature such as occurs after a hot bath or when using a hairdryer (Eunson et al, 2000).…”

“…The molecular mechanisms underlying EA1 have been established by determining the functional properties of wild-type (WT) and several mutant channels in Xenopus oocytes or mammalian cell lines (Adelman et al, 1995;D'Adamo et al, 1998;Zerr et al, 1998;D'Adamo et al, 1999;Zuberi et al, 1999;Eunson et al, 2000;Manganas et al, 2001;Cusimano et al, 2004;Imbrici et al, 2003Imbrici et al, , 2007Imbrici et al, , 2008Imbrici et al, , 2006Imbrici et al, , 2007Imbrici et al, , 2008Imbrici et al, , 2009 (Petersson et al, 2003); S309T is a missense mutation identified in autosomal-dominant myokymia and seizures rats: rKv1.1 S309T/+ (Ishida et al, 2012); V408A is a mutation identified in individuals with EA1 that was inserted into the murine Kcna1 to generate a knockin animal model of the disease: mKv1.1 V408A/+ (Herson et al, 2003).…”

“…The expression of molecules of the insulin-like growth factor system, transforming growth factor-β1 (Petersson et al, 1999) as well as several trophic neuropeptides (Petersson et al, 2000) are significantly altered in the mceph/mceph mouse brain. Remarkably, an 11-base pair deletion in the Kcna1 gene of mceph/ mceph mice has been identified using a positional cloning approach (Petersson et al, 2003). The mutation leads to a frame shift and to a premature stop codon that was predicted to truncate the protein at amino acid 230 (of 495) (Figure 51.3).…”