TY - JOUR
T1 - Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis
AU - Roepke, Torsten K.
AU - King, Elizabeth C.
AU - Reyna-Neyra, Andrea
AU - Paroder, Monika
AU - Purtell, Kerry
AU - Koba, Wade
AU - Fine, Eugene
AU - Lerner, Daniel J.
AU - Carrasco, Nancy
AU - Abbott, Geoffrey W.
N1 - Funding Information:
G.W.A. is supported by the US National Heart, Lung, and Blood Institute (HL079275) and the American Heart Association (0855756D). N.C. is supported by the US National Institute of Diabetes and Digestive and Kidney Diseases (DK41544) and the US National Cancer Institute (CA098390). M.P. is supported by US National Institutes of Health Medical Scientist Training Grant 5T32GM002788. We are grateful for expert technical assistance from S. Backovic, L. Cohen-Gould, G. J.-S. Abbott, K. La Perle, the Molecular Cytology Core Facility of Memorial Sloan-Kettering Cancer Center and C. Basson and J. Chen (WCMC Center for Molecular Cardiology Small Animal Physiology Core Facility). We also thank T. Denecke for interpreting the radiographs and B. Abbott for critical reading of the manuscript.
PY - 2009
Y1 - 2009
N2 - Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T 4) content and halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T 3) and T 4 administration to pups, by supplementing dams with T 4 before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams; conversely, these symptoms were elicited in Kcne2+/+ pups by feeding exclusively from Kcne2/ dams. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2-and KCNQ1-linked human cardiac arrhythmias.
AB - Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T 4) content and halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T 3) and T 4 administration to pups, by supplementing dams with T 4 before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams; conversely, these symptoms were elicited in Kcne2+/+ pups by feeding exclusively from Kcne2/ dams. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2-and KCNQ1-linked human cardiac arrhythmias.
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U2 - 10.1038/nm.2029
DO - 10.1038/nm.2029
M3 - Article
C2 - 19767733
AN - SCOPUS:70350572844
SN - 1078-8956
VL - 15
SP - 1186
EP - 1194
JO - Nature Medicine
JF - Nature Medicine
IS - 10
ER -