%0 Journal Article %1 Mohl_2003_634 %A Mohler, Peter J %A Schott, Jean-Jacques %A Gramolini, Anthony O %A Dilly, Keith W %A Guatimosim, Silvia %A duBell, William H %A Song, Long-Sheng %A Haurogn�, Karine %A Kyndt, Florence %A Ali, Mervat E %A Rogers, Terry B %A Lederer, W. J. %A Escande, Denis %A Marec, Herve Le %A Bennett, Vann %D 2003 %J Nature %K 1,4,5-Trisphosphate ATPase, Action Animals; Ankyrins, Binding; Bradycardia, Calcium Cardiac, Channels, Cytoplasmic Death, Electrocardiography; Exchanger, Female; Heart Heart, Heterozygote; Humans; Inositol Long Male; Mice; Mutation, Myocardium, Nuclear, Patch-Clamp Pedigree; Phenotype; Potentials; Protein QT Rate; Receptors, Receptors; Signaling; Sodium-Calcium Sodium-Potassium-Exchanging Sudden, Syndrome, Techniques; and classification/genetics/metabolism/physiopathology; complications/genetics/metabolism/physiopathology; etiology; genetics/physiology; genetics; metabolism metabolism/pathology; metabolism; physiopathology; %N 6923 %P 634--639 %R 10.1038/nature01335 %T Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. %U http://dx.doi.org/10.1038/nature01335 %V 421 %X Mutations in ion channels involved in the generation and termination of action potentials constitute a family of molecular defects that underlie fatal cardiac arrhythmias in inherited long-QT syndrome. We report here that a loss-of-function (E1425G) mutation in ankyrin-B (also known as ankyrin 2), a member of a family of versatile membrane adapters, causes dominantly inherited type 4 long-QT cardiac arrhythmia in humans. Mice heterozygous for a null mutation in ankyrin-B are haploinsufficient and display arrhythmia similar to humans. Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing overall protein level. Ankyrin-B mutation also leads to altered Ca$^2+$ signalling in adult cardiomyocytes that results in extrasystoles, and provides a rationale for the arrhythmia. Thus, we identify a new mechanism for cardiac arrhythmia due to abnormal coordination of multiple functionally related ion channels and transporters.

@article{Mohl_2003_634, abstract = {Mutations in ion channels involved in the generation and termination of action potentials constitute a family of molecular defects that underlie fatal cardiac arrhythmias in inherited long-QT syndrome. We report here that a loss-of-function (E1425G) mutation in ankyrin-B (also known as ankyrin 2), a member of a family of versatile membrane adapters, causes dominantly inherited type 4 long-QT cardiac arrhythmia in humans. Mice heterozygous for a null mutation in ankyrin-B are haploinsufficient and display arrhythmia similar to humans. Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing overall protein level. Ankyrin-B mutation also leads to altered {C}a$^{2+}$ signalling in adult cardiomyocytes that results in extrasystoles, and provides a rationale for the arrhythmia. Thus, we identify a new mechanism for cardiac arrhythmia due to abnormal coordination of multiple functionally related ion channels and transporters.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Mohler, Peter J and Schott, Jean-Jacques and Gramolini, Anthony O and Dilly, Keith W and Guatimosim, Silvia and duBell, William H and Song, Long-Sheng and Haurogn�, Karine and Kyndt, Florence and Ali, Mervat E and Rogers, Terry B and Lederer, W. J. and Escande, Denis and Marec, Herve Le and Bennett, Vann}, biburl = {https://www.bibsonomy.org/bibtex/2767c0c03f80b18a37c5d6ad0200f2e01/hake}, description = {The whole bibliography file I use.}, doi = {10.1038/nature01335}, file = {Mohl_2003_634.pdf:Mohl_2003_634.pdf:PDF}, institution = {Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA.}, interhash = {abd560fa40ac2e38c632a1b701a4e2d2}, intrahash = {767c0c03f80b18a37c5d6ad0200f2e01}, journal = {Nature}, keywords = {1,4,5-Trisphosphate ATPase, Action Animals; Ankyrins, Binding; Bradycardia, Calcium Cardiac, Channels, Cytoplasmic Death, Electrocardiography; Exchanger, Female; Heart Heart, Heterozygote; Humans; Inositol Long Male; Mice; Mutation, Myocardium, Nuclear, Patch-Clamp Pedigree; Phenotype; Potentials; Protein QT Rate; Receptors, Receptors; Signaling; Sodium-Calcium Sodium-Potassium-Exchanging Sudden, Syndrome, Techniques; and classification/genetics/metabolism/physiopathology; complications/genetics/metabolism/physiopathology; etiology; genetics/physiology; genetics; metabolism metabolism/pathology; metabolism; physiopathology;}, month = Feb, number = 6923, pages = {634--639}, pdf = {Mohl_2003_634.pdf}, pii = {nature01335}, pmid = {12571597}, timestamp = {2009-06-03T11:21:23.000+0200}, title = {Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.}, url = {http://dx.doi.org/10.1038/nature01335}, volume = 421, year = 2003 }