A novel Kir2.6 mutation associated with hypokalemic periodic paralysis

Zheng, Jieyun; Liang, Zonglai; Hou, Ying; Liu, Fuchen; Hu, Yuanyuan; Lin, Pengfei; Yan, Chuanzhu

doi:10.1016/j.clinph.2016.03.008

Cited by 6 publications

(3 citation statements)

References 20 publications

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“…Nevertheless, TTP and SPP are closely related since they appear to share a number of susceptibility genes [ 197 , 198 , 199 , 200 ]. Mutations in the KCNJ18 gene have been reported in a few cases with TPP [ 201 , 202 , 203 , 204 ]. The KCNJ18 gene encodes the skeletal muscle inward-rectifier K channel Kir2.6, the expression of which is enhanced by thyroid hormone (T 3 ) through a promoter response element.…”

Section: Potassium Channel-related Myopathiesmentioning

confidence: 99%

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Maggi

Bonanno

Altamura

et al. 2021

Cells

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Skeletal muscle ion channelopathies (SMICs) are a large heterogeneous group of rare genetic disorders caused by mutations in genes encoding ion channel subunits in the skeletal muscle mainly characterized by myotonia or periodic paralysis, potentially resulting in long-term disabilities. However, with the development of new molecular technologies, new genes and new phenotypes, including progressive myopathies, have been recently discovered, markedly increasing the complexity in the field. In this regard, new advances in SMICs show a less conventional role of ion channels in muscle cell division, proliferation, differentiation, and survival. Hence, SMICs represent an expanding and exciting field. Here, we review current knowledge of SMICs, with a description of their clinical phenotypes, cellular and molecular pathomechanisms, and available treatments.

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Section: Potassium Channel-related Myopathiesmentioning

confidence: 99%

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Maggi

Bonanno

Altamura

et al. 2021

Cells

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“…Defects in ion channels are increasingly implicated in endocrine diseases. For example, dysfunctional or inactive K-ATP channel function due to mutations in KIR6.2/SUR1 genes leads to congenital hyperinsulinism and/or neonatal diabetes, and defects in potassium channel KCNJ18 underlie periodic hypokalemic paralysis ( 1 – 3 ). We recently reported that two specific mutations in KCNQ1 , a gene encoding the alpha subunit of a voltage-gated K+ channel (Kv7.1), result in a gain-of-function in patch clamp analyses and cause pituitary hormone deficiency and maternally inherited gingival fibromatosis ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

The Role of KCNQ1 Mutations and Maternal Beta Blocker Use During Pregnancy in the Growth of Children With Long QT Syndrome

et al. 2018

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ObjectiveTwo missense mutations in KCNQ1, an imprinted gene that encodes the alpha subunit of the voltage-gated potassium channel Kv7.1, cause autosomal dominant growth hormone deficiency and maternally inherited gingival fibromatosis. We evaluated endocrine features, birth size, and subsequent somatic growth of patients with long QT syndrome 1 (LQT1) due to loss-of-function mutations in KCNQ1.DesignMedical records of 104 patients with LQT1 in a single tertiary care center between 1995 and 2015 were retrospectively reviewed.MethodsClinical and endocrine data of the LQT1 patients were included in the analyses.ResultsAt birth, patients with a maternally inherited mutation (n = 52) were shorter than those with paternal inheritance of the mutation (n = 29) (birth length, −0.70 ± 1.1 SDS vs. −0.2 ± 1.0 SDS, P < 0.05). Further analyses showed, however, that only newborns (n = 19) of mothers who had received beta blockers during pregnancy were shorter and lighter at birth than those with paternal inheritance of the mutation (n = 29) (−0.89 ± 1.0 SDS vs. −0.20 ± 1.0 SDS, P < 0.05; and 3,173 ± 469 vs. 3,515 ± 466 g, P < 0.05). Maternal beta blocker treatment during the pregnancy was also associated with lower cord blood TSH levels (P = 0.011) and significant catch-up growth during the first year of life (Δ0.08 SDS/month, P = 0.004). Later, childhood growth of the patients was unremarkable.ConclusionLoss-of-function mutations in KCNQ1 are not associated with abnormalities in growth, whereas maternal beta blocker use during pregnancy seems to modify prenatal growth of LQT1 patients—a phenomenon followed by catch-up growth after birth.

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“…The most common form of sporadic PP (SPP) is the thyrotoxic PP (TPP), which is clinically similar to hypoPP or ATS. TPP can result from mutations in the KCNJ18 gene, encoding Kir2.6 channels 5 – 7 that are under transcriptional regulation of thyroid hormones. 8 TPP-causing mutations in Kir2.6 include loss-of-function mutations, similar to that in Kir2.1 and ATS, but also gain-of-function mutations 8 that are believed to hyperpolarize the skeletal muscle, leading to a reduced excitability, as the membrane potential is too far from the action potential threshold.…”

mentioning

confidence: 99%

Increased KCNJ18 promoter activity as a mechanism in atypical normokalemic periodic paralysis

Soufi¹,

Ruppert

Rinné

et al. 2018

Neurol Genet

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ObjectiveTo identify the genetic basis of a patient with symptoms of normokalemic sporadic periodic paralysis (PP) and to study the effect of KCNJ18 mutations.MethodsA candidate gene approach was used to identify causative gene mutations, using Sanger sequencing. KCNJ18 promoter activity was analyzed in transfected HEK293 cells with a luciferase assay, and functional analysis of Kir2.6 channels was performed with the two-electrode voltage-clamp technique.ResultsAlthough we did not identify harmful mutations in SCN4A, CACNA1S, KCNJ2 and KCNE3, we detected a monoallelic four-fold variant in KCNJ18 (R39Q/R40H/A56E/I249V), together with a variant in the respective promoter of this channel (c.-542T/A). The exonic variants in Kir2.6 did not alter the channel function; however, luciferase assays revealed a 10-fold higher promoter activity of the c.-542A promoter construct, which is likely to cause a gain-of-function by increased expression of Kir2.6. We found that reducing extracellular K+ levels causes a paradoxical reduction in outward currents, similar to that described for other inward rectifying K+ channels. Thus, reducing the extracellular K+ levels might be a therapeutic strategy to antagonize the transcriptionally increased KCNJ18 currents. Consistently, treatment of the patient with K+ reducing drugs dramatically improved the health situation and prevented PP attacks.ConclusionsWe show that a promoter defect in the KCNJ18 gene is likely to cause periodic paralysis, as the observed transcriptional upregulation will be linked to increased Kir2.6 function. This concept is further supported by our observation that most of the PP attacks in our patient disappeared on medical treatment with K+ reducing drugs.

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A novel Kir2.6 mutation associated with hypokalemic periodic paralysis

Cited by 6 publications

References 20 publications

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

The Role of KCNQ1 Mutations and Maternal Beta Blocker Use During Pregnancy in the Growth of Children With Long QT Syndrome

Increased KCNJ18 promoter activity as a mechanism in atypical normokalemic periodic paralysis

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