Alternative pre-mRNA splicing
of ion channels


Executive Summary

This collaboration investigates how the read-out of genetic information is modulated by alternative splicing through primate-specific genetic elements and cellular activity. Bioinformatics, genetics, molecular biology and electrophysiology experts will jointly explore the reciprocal relationship between alternative splicing and cellular activity as it is influenced by mutations and mobile genetic elements. By alternative splicing, mammalian organisms generate a complex and highly plastic expression pattern of ion channels that underlies membrane functioning in epithelial and nerve cells. In the nervous system, this mechanism contributes to the physiological adaptation of motor coordination and higher cognitive functions. Failure of cellular systems to appropriately adapt alternative splicing patterns to modified stimuli may either result in disease or aggravate pathological phenotypes.

Indeed, aberrant alternative splicing is increasingly recognized as a cause and consequence of human disease, including neurological disorders and cystic fibrosis. Novel therapeutic approaches demonstrated that missplicing events can be reversed, but animal models to test further treatments are still lacking. The project will lead to

  1. Improved understanding of how the genetic information is used to generate and modify higher human cognitive functions,

  2. Insights in the molecular mechanisms underlying growth and adaptation processes.

  3. Diagnostic avenues to genes that modulate the clinical severity of hereditary disease, and

  4. Novel approaches for retrieval of normal alternative splicing in patients with inherited disorders.

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