Abstracts

Mutations of ion channel genes are an important cause of inherited epilepsy and cardiac arrhythmia syndromes. It is our hypothesis that a defined group of ion channelopathies may underlie a specific phenotype of seizures combined with cardiac arrhythmias. The objective of this study is to verify the cerebral expression of two potassium ion genes linked to inherited cardiac rhythm disorders that are candidates for this syndrome.
We performed regional mapping of KvLQT1 and KCNE1 genes, both linked to inherited LQT syndromes, in the developing and adult mouse brain and in dissected adult human brain regions obtained from post-mortem tissue specimens using the RT-PCR method. RNA was obtained from the whole brain of P0, P10 mice and from subregions of adult mouse brain (female C57BL/6). Spinal cord was studied in P10 and adult mice. Human RNA expression profiles were assessed in samples from neocortex, hippocampus, cerebellum and spinal cord. RNA samples from mouse and human heart were used as internal positive controls.
KvLQT1 mutations account for about 50% of all LQT cases, yet the expression of this gene in brain has never been unequivocally documented. We confirmed the expression of two functional KvLQT1 isoforms in human brain. Isoform 1, described in heart and several other peripheral tissues was present in all brain regions studied. Isoform 2, believed to be heart specific was found in hippocampus, frontal, parietal, and occipital neocortex and at a lower levels in temporal cortex and spinal cord. Additional splice variants of uncertain functional significance were also noted. In mouse, we found two distinct isoforms expressed in heart, of which only one was clearly present in all CNS samples studied. Definite KvLQT1 expression in CNS was obvious in P0 animals and at older ages. Mutations in the I[sub]ks[/sub] channel [beta] subunit (MinK) are a less frequent source of human LQT mutations, however when present their clinical impact is profound. We found the gene to be expressed in all human CNS regions as well as in mouse brain samples through early development. MinK RNA expression was weak in the P10 and adult mouse spinal cords.
Mutations in LQT genes alter membrane excitability and cause cardiac arrhythmias. Of seven LQT genes identified to date (SCN5A, KvLQT1, HERG, MinkA, MiRP1, Kir2.1, AnkB), all had confirmed brain expression except KVLQT1 and MinK. We determined the unequivocal presence of these two LQT genes in mouse and human brain. Moreover, their developmental and regional expression patterns support our hypothesis that LQT genes co-expressed in heart and brain are likely candidate genes for the clinical phenotype of seizures combined with cardiac arrhythmias.
[Supported by: American Epilepsy Society/Epilepsy Foundation (AMG), Blue Bird Circle, Charles A. Dana Foundation (JLN). ]