Identification and Functional Characterization of Kir2.6 Mutations Associated with Non-familial Hypokalemic Periodic Paralysis

Cheng, Chih Jen; Lin, Shih Hua; Lo, Yi Fen; Yang, Sung Sen; Hsu, Yi-Chih; Cannon, Stephen C.; Huang, Chou Long

doi:10.1074/jbc.m111.249656

Cited by 53 publications

(37 citation statements)

References 32 publications

(31 reference statements)

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“…Recent studies show that loss-of-function mutations in Kir2.6 cause non-familial HypoPP, TPP and SPP. 49,53 As illustrated in Figure 1E and 1F, reduced I Kir current through mutant Kir would have the same impact as enhanced I Leak with respect to the effect of creating imbalance between outward K + current and inward leak current. That is, during hypokalemia in patients with TPP and SPP, outward K + currents through mutant Kir is always smaller than the inward leak current, and balance between outward and inward currents can only be reached if resting membrane potential is shifted to depolarized membrane potential where outward K + current is mediated by K V (Figure 1F).…”

Section: K+ Channels and Extracellular Potassium Homeostasismentioning

confidence: 95%

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Extracellular Potassium Homeostasis: Insights from Hypokalemic Periodic Paralysis

Cheng

Kuo

Huang

2013

Seminars in Nephrology

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The extracellular potassium makes up only about 2% of the total body potassium store. The majority of the body potassium is distributed in the intracellular space, and of which about 80% is in skeletal muscle. Movement of potassium in and out of skeletal muscle thus plays a pivotal role in extracellular potassium homeostasis. The exchange of potassium between the extracellular space and skeletal muscle is mediated by specific membrane transporters. These include potassium uptake by Na+, K+-ATPase and release by inward rectifier K+ channels. These processes are regulated by circulating hormones, peptides, ions, and by physical activity of muscle as well as dietary potassium intake. Pharmaceutical agents, poisons and disease conditions also affect the exchange and alter extracellular potassium concentration. Here, we review extracellular potassium homeostasis focusing on factors and conditions that influence the balance of potassium movement in skeletal muscle. Recent findings that mutations of a skeletal muscle-specific inward rectifier K+ channel cause hypokalemic periodic paralysis provide interesting insights into the role of skeletal muscle in extracellular potassium homeostasis. These recent findings will be reviewed.

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Section: K+ Channels and Extracellular Potassium Homeostasismentioning

confidence: 95%

“…The mechanism of paradoxical depolarization in TPP and SPP patients has provided unique insights into the pathogenesis of severe hypokalemia in HypoPP. 53 …”

Section: K+ Channels and Extracellular Potassium Homeostasismentioning

confidence: 99%

Extracellular Potassium Homeostasis: Insights from Hypokalemic Periodic Paralysis

Cheng

Kuo

Huang

2013

Seminars in Nephrology

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“…While TPP is the most common cause of periodic paralysis, only a minority of patients have an identified mutation in Kir2.6. Moreover, genetic screening of sporadic non-familial HypoPP, and without thyrotoxicosis, has revealed mutations of Kir2.6 (39). …”

Section: Potassium Channelopathies Of Skeletal Musclementioning

confidence: 99%

“…In the original report of Kir2.6 mutations associated with TPP, one was a frameshift in the pore loop yielding a nonfunctional transcript, one missense mutation resulted in moderately reduced current amplitude, and the remaining four mutations had no discernable effect (218). Subsequent screening of KCNJ18 in patients with TPP or sporadic HypoPP led to the identification of 3 additional missense mutations of Kir2.6, and all had loss-of-function changes with dominant negative inhibition of WT Kir2.6 and Kir2.1 (39). Another proposal is that Kir2.6 regulates the surface expression of Kir2.1 and Kir2.2 (49).…”

Section: Potassium Channelopathies Of Skeletal Musclementioning

confidence: 99%

Channelopathies of Skeletal Muscle Excitability

Cannon

2015

Comprehensive Physiology

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Familial disorders of skeletal muscle excitability were initially described early in the last century and are now known to be caused by mutations of voltage-gated ion channels. The clinical manifestations are often striking, with an inability to relax after voluntary contraction (myotonia) or transient attacks of severe weakness (periodic paralysis). An essential feature of these disorders is fluctuation of symptoms that are strongly impacted by environmental triggers such as exercise, temperature, or serum K+ levels. These phenomena have intrigued physiologists for decades, and in the past 25 years the molecular lesions underlying these disorders have been identified and mechanistic studies are providing insights for therapeutic strategies of disease modification. These familial disorders of muscle fiber excitability are “channelopathies” caused by mutations of a chloride channel (ClC-1), sodium channel (NaV1.4), calcium channel (CaV1.1) and several potassium channels (Kir2.1, Kir2.6, Kir3.4). This review provides a synthesis of the mechanistic connections between functional defects of mutant ion channels, their impact on muscle excitability, how these changes cause clinical phenotypes, and approaches toward therapeutics.

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“…3 Possible mechanisms for hypokalemia in TPP include activation of the Na + ,K + -ATPase pump by thyroid hormone, a hyperadrenergic state, and hyperinsulinemia in combination with reduced K + efflux into the skeletal muscle. [4][5][6][7] Several factors have been reported to increase Na + ,K + -ATPase activity and potentially precipitate an attack of TPP, including a high-carbohydrate diet and strenuous exercise (Table 1). 3,[8][9][10] The triggering of an attack of undiagnosed TPP by b 2 -adrenergic bronchodilators has, to our knowledge, not been reported previously.…”

Section: Ré Sumémentioning

confidence: 99%

Thyrotoxic periodic paralysis triggered by β2- adrenergic bronchodilators

Yeh

Chiang

Wang

et al. 2014

CJEM

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Hypokalemic periodic paralysis is the most common form of periodic paralysis and is characterized by attacks of muscle paralysis associated with a low serum potassium (K + ) level due to an acute intracellular shifting. Thyrotoxic periodic paralysis (TPP), characterized by the triad of muscle paralysis, acute hypokalemia, and hyperthyroidism, is one cause of hypokalemic periodic paralysis. The triggering of an attack of undiagnosed TPP by b 2 -adrenergic bronchodilators has, to our knowledge, not been reported previously. We describe two young men who presented to the emergency department with the sudden onset of muscle paralysis after administration of inhaled b 2 -adrenergic bronchodilators for asthma. In both cases, the physical examination revealed an enlarged thyroid gland and symmetrical flaccid paralysis with areflexia of lower extremities. Hypokalemia with low urine K + excretion and normal blood acid-base status was found on laboratory testing, suggestive of an intracellular shift of K + , and the patients' muscle strength recovered at serum K + concentrations of 3.0 and 3.3 mmol/L. One patient developed hyperkalemia after a total potassium chloride supplementation of 110 mmol. Thyroid function testing was diagnostic of primary hyperthyroidism due to Graves disease in both cases. These cases illustrate that b 2 -adrenergic bronchodilators should be considered a potential precipitant of TPP. RÉ SUMÉLa paralysie pé riodique hypokalié mique est la forme la plus fré quente de paralysie pé riodique, et elle se caracté rise par des accè s de paralysie musculaire, associé s à de faibles taux sé riques de potassium (K + ) et attribuables à un passage soudain des ions dans le compartiment intracellulaire. La paralysie pé riodique thyrotoxique (PPT), qui se caracté rise par la triade de signes suivants, paralysie musculaire, hypokalié mie aiguë , et hyperthyroïdie, est une cause de paralysie pé riodique hypokalié mique. À notre connaissance, le dé clenchement d'un accè s de PPT, non diagnostiqué e jusque là , par des bronchodilatateurs b 2 adré nergiques n'avait jamais é té signalé auparavant. Il sera question, dans le pré sent article, du cas de deux jeunes hommes examiné s au service des urgences pour un accè s soudain de paralysie musculaire aprè s l'administration de bronchodilatateurs b 2 adré nergiques en aé rosol pour de l'asthme. Dans les deux cas, l'examen physique avait mis en é vidence une hypertrophie de la glande thyroïde et une paralysie flasque symé trique, accompagné e d'une aré flexie des membres infé rieurs. Les examens de laboratoire ont ré vé lé une hypokalié mie, accompagné e d'une faible excré tion urinaire de K + , mais un é quilibre acido-basique sanguin normal, ce qui est l'indice d'un passage intracellulaire de K + ; la force musculaire est revenue chez les deux patients une fois que les taux sé riques de K + eurent atteint 3.0 et 3.3 mmol/L. Une hyperkalié mie s'est produite chez l'un des patients aprè s une recharge totale de chlorure de potassium de 110 mmol. Dans les deux cas, l'é pre...

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Identification and Functional Characterization of Kir2.6 Mutations Associated with Non-familial Hypokalemic Periodic Paralysis

Cited by 53 publications

References 32 publications

Extracellular Potassium Homeostasis: Insights from Hypokalemic Periodic Paralysis

Extracellular Potassium Homeostasis: Insights from Hypokalemic Periodic Paralysis

Channelopathies of Skeletal Muscle Excitability

Thyrotoxic periodic paralysis triggered by β2- adrenergic bronchodilators

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