TY - JOUR
T1 - A mutation in telethonin alters Nav1.5 function
AU - Mazzone, Amelia
AU - Strege, Peter R.
AU - Tester, David J.
AU - Bernard, Cheryl E.
AU - Faulkner, Georgine
AU - De Giorgio, Roberto
AU - Makielski, Jonathan C.
AU - Stanghellini, Vincenzo
AU - Gibbons, Simon J.
AU - Ackerman, Michael J.
AU - Farrugia, Gianrico
PY - 2008/6/13
Y1 - 2008/6/13
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M801744200
DO - 10.1074/jbc.M801744200
M3 - Article
C2 - 18408010
AN - SCOPUS:47749102965
SN - 0021-9258
VL - 283
SP - 16537
EP - 16544
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 24
ER -