A mutation in telethonin alters Nav1.5 function

Amelia Mazzone, Peter R. Strege, David J. Tester, Cheryl E. Bernard, Georgine Faulkner, Roberto De Giorgio, Jonathan C. Makielski, Vincenzo Stanghellini, Simon J. Gibbons, Michael J. Ackerman, Gianrico Farrugia

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


Excitable cells express a variety of ion channels that allow rapid exchange of ions with the extracellular space. Opening of Na+ channels in excitable cells results in influx of Na+ and cellular depolarization. The function of Nav1.5, an Na+ channel expressed in the heart, brain, and gastrointestinal tract, is altered by interacting proteins. The pore-forming α-subunit of this channel is encoded by SCN5A. Genetic perturbations in SCN5A cause type 3 long QT syndrome and type 1 Brugada syndrome, two distinct heritable arrhythmia syndromes. Mutations in SCN5A are also associated with increased prevalence of gastrointestinal symptoms, suggesting that the Na+ channel plays a role in normal gastrointestinal physiology and that alterations in its function may cause disease. We collected blood from patients with intestinal pseudo-obstruction (a disease associated with abnormal motility in the gut) and screened for mutations in SCN5A and ion channel-interacting proteins. A 42-year-old male patient was found to have a mutation in the gene TCAP, encoding for the small protein telethonin. Telethonin was found to be expressed in the human gastrointestinal smooth muscle, co-localized with Nav1.5, and co-immunoprecipitated with sodium channels. Expression of mutated telethonin, when co-expressed with SCN5A in HEK 293 cells, altered steady state activation kinetics of SCN5A, resulting in a doubling of the window current. These results suggest a new role for telethonin, namely that telethonin is a sodium channel-interacting protein. Also, mutations in telethonin can alter Nav1.5 kinetics and may play a role in intestinal pseudo-obstruction.

Original languageEnglish (US)
Pages (from-to)16537-16544
Number of pages8
JournalJournal of Biological Chemistry
Issue number24
StatePublished - Jun 13 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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