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 John Ackerman, Gianrico Farrugia

Research output: Contribution to journalArticle

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Abstract

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
Volume283
Issue number24
DOIs
StatePublished - Jun 13 2008

Fingerprint

Intestinal Pseudo-Obstruction
Mutation
Sodium Channels
Ion Channels
Romano-Ward Syndrome
Proteins
Brugada Syndrome
Kinetics
Gene encoding
HEK293 Cells
Ion Exchange
Physiology
Depolarization
Extracellular Space
Smooth Muscle
Muscle
Gastrointestinal Tract
Cardiac Arrhythmias
Brain
Blood

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Mazzone, A., Strege, P. R., Tester, D. J., Bernard, C. E., Faulkner, G., De Giorgio, R., ... Farrugia, G. (2008). A mutation in telethonin alters Nav1.5 function. Journal of Biological Chemistry, 283(24), 16537-16544. https://doi.org/10.1074/jbc.M801744200

A mutation in telethonin alters Nav1.5 function. / Mazzone, Amelia; Strege, Peter R.; Tester, David J.; Bernard, Cheryl E.; Faulkner, Georgine; De Giorgio, Roberto; Makielski, Jonathan C.; Stanghellini, Vincenzo; Gibbons, Simon J.; Ackerman, Michael John; Farrugia, Gianrico.

In: Journal of Biological Chemistry, Vol. 283, No. 24, 13.06.2008, p. 16537-16544.

Research output: Contribution to journalArticle

Mazzone, A, Strege, PR, Tester, DJ, Bernard, CE, Faulkner, G, De Giorgio, R, Makielski, JC, Stanghellini, V, Gibbons, SJ, Ackerman, MJ & Farrugia, G 2008, 'A mutation in telethonin alters Nav1.5 function', Journal of Biological Chemistry, vol. 283, no. 24, pp. 16537-16544. https://doi.org/10.1074/jbc.M801744200
Mazzone A, Strege PR, Tester DJ, Bernard CE, Faulkner G, De Giorgio R et al. A mutation in telethonin alters Nav1.5 function. Journal of Biological Chemistry. 2008 Jun 13;283(24):16537-16544. https://doi.org/10.1074/jbc.M801744200
Mazzone, Amelia ; Strege, Peter R. ; Tester, David J. ; Bernard, Cheryl E. ; Faulkner, Georgine ; De Giorgio, Roberto ; Makielski, Jonathan C. ; Stanghellini, Vincenzo ; Gibbons, Simon J. ; Ackerman, Michael John ; Farrugia, Gianrico. / A mutation in telethonin alters Nav1.5 function. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 24. pp. 16537-16544.
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