title: 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.
authors.affiliation: Neurogenetic Unit, Department of Molecular Medicine, CMM, L8:00, Karolinska Institutet, 171 76 Stockholm, Sweden. susanna.petersson@licr.ki.se
authors.forename: Susanna
authors.initials: S
authors.lastname: Petersson
authors.forename: Ann-Sophie
authors.initials: AS
authors.lastname: Persson
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Johansen
authors.forename: Martin
authors.initials: M
authors.lastname: Ingvar
authors.forename: Johanna
authors.initials: J
authors.lastname: Nilsson
authors.forename: Göran
authors.initials: G
authors.lastname: Klement
authors.forename: Peter
authors.initials: P
authors.lastname: Arhem
authors.forename: Martin
authors.initials: M
authors.lastname: Schalling
authors.forename: Catharina
authors.initials: C
authors.lastname: Lavebratt
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000254:growth & development / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics*; D017353:Gene Deletion; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism; D051662:Kv1.1 Potassium Channel; D051663:Kv1.2 Potassium Channel; D051664:Kv1.3 Potassium Channel; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D009421:Nervous System Malformations / Q000235:genetics* / Q000378:metabolism; D015221:Potassium Channels / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D017434:Protein Structure, Tertiary / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012640:Seizures / Q000235:genetics / Q000378:metabolism
chemical_list: C496947:Kcna1 protein, mouse; C496970:Kcna2 protein, mouse; C496974:Kcna3 protein, mouse; D051663:Kv1.2 Potassium Channel; D051664:Kv1.3 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D012333:RNA, Messenger; D051662:Kv1.1 Potassium Channel