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Bioinformatic analysis of human CNS-expressed ion channels as candidates for episodic nervous system disorders

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Abstract

As monogenic forms of episodic nervous system disorders are often caused by ion channel mutations, we looked for features of human central nervous system (CNS) expressed ion channels that further our understanding of those phenotypes. To this end, we compared human ion channels with other CNS-expressed genes, which we categorized according to the existence of transmembrane domains. When looking at the phylogenetic distribution of these genes, we observed an increased percentage of ion channels that exist in vertebrate genomes while missing in invertebrate genomes. Because we hypothesized that this pattern may relate to a more specific expression, we searched for characteristics of ion channels that indicate a tighter expression regulation. We found that ion channels have longer intron and protein sequences, features typical of genes with more specific expression. In addition, ion channels have increased human–rodent conservation around their transcription start site, as indicated by a higher fraction of conserved noncoding regions. This points to a high relevance of mutations that regulate ion channel expression. When we finally asked whether vertebrate-specific diversification is also displayed by non-ion channel genes with important roles in the CNS, we found a similar phylogenetic distribution. This concordant phylogenetic pattern suggests that vertebrate-specific adaptations may account for a large part of the shared genetic basis of episodic CNS disorders, including monogenic and genetically complex disease manifestations. Consequently, this phylogenetic pattern may contribute to the prioritization of candidate genes in human genetic studies of episodic CNS disorders.

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Acknowledgements

We thank Jimmy Holder, Devon Ryan, and Yun Freudenberg-Hua and the two anonymous reviewers for their comments on the manuscript. This work was supported by the Howard Hughes Medical Institute and a Sandler Neurogenetics grant. LJP is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Laboratories of Neurogenetics, Department of Neurology, Institute of Human Genetics, University of California San Francisco, 1550 4th Street, San Francisco, CA, 94158-2922, USA

    Jan Freudenberg, Ying-Hui Fu & Louis J. Ptáček

  2. Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA

    Louis J. Ptáček

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  1. Jan Freudenberg
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  2. Ying-Hui Fu
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  3. Louis J. Ptáček
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Correspondence to Jan Freudenberg or Louis J. Ptáček.

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Freudenberg, J., Fu, YH. & Ptáček, L.J. Bioinformatic analysis of human CNS-expressed ion channels as candidates for episodic nervous system disorders. Neurogenetics 8, 159–168 (2007). https://doi.org/10.1007/s10048-007-0082-4

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