Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis.
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 (T4) 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 (T3) and T4 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.
Roepke
Torsten K
TK
Greenberg Division of Cardiology, Department of Medicine and Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, USA.
King
Elizabeth C
EC
Reyna-Neyra
Andrea
A
Paroder
Monika
M
Purtell
Kerry
K
Koba
Wade
W
Fine
Eugene
E
Lerner
Daniel J
DJ
Carrasco
Nancy
N
Abbott
Geoffrey W
GW
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D006579:Heterozygote; D006720:Homozygote; D007037:Hypothyroidism / Q000235:genetics / Q000378:metabolism; D007774:Lactation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008892:Milk / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D017384:Sequence Deletion; D013961:Thyroid Gland / Q000378:metabolism* / Q000648:ultrastructure; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000235:genetics / Q000378:metabolism
C489620:Kcne2 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D013963:Thyroid Hormones; D014284:Triiodothyronine