title: A mutation in telethonin alters Nav1.5 function.
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 Na(v)1.5, an Na(+) channel expressed in the heart, brain, and gastrointestinal tract, is altered by interacting proteins. The pore-forming alpha-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 Na(v)1.5, 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 Na(v)1.5 kinetics and may play a role in intestinal pseudo-obstruction.
authors.affiliation: Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Amelia
authors.initials: A
authors.lastname: Mazzone
authors.forename: Peter R
authors.initials: PR
authors.lastname: Strege
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Bernard
authors.forename: Georgine
authors.initials: G
authors.lastname: Faulkner
authors.forename: Roberto
authors.initials: R
authors.lastname: De Giorgio
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Stanghellini
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Gibbons
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D064211:Connectin; D004252:DNA Mutational Analysis; D005822:Genetic Vectors; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D009130:Muscle, Smooth / Q000378:metabolism; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000737:chemistry* / Q000378:metabolism
chemical_list: D064211:Connectin; D007473:Ion Channels; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; C577292:TCAP protein, human