A syndrome of congenital hyperinsulinism and rhabdomyolysis is caused by<i>KCNJ11</i>mutation

Albaqumi, Mamdouh; Alhabib, Fatimah A.; Shamseldin, Hanan E.; Mohammed, Firdous; Alkuraya, Fowzan S.

doi:10.1136/jmedgenet-2013-102085

Cited by 7 publications

(6 citation statements)

References 20 publications

(21 reference statements)

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“…Loss-of-function mutations in Kir6.2 and SUR1 are associated with congenital hyperinsulinism (Nestorowicz et al, 1996;Thomas et al, 1996;Dunne et al, 1997;Nestorowicz et al, 1997). Interestingly, there does not appear to be any obvious skeletal muscle defect, although Albaqumi et al (2014) described a family with congenital hyperinsulinism and rhabdomyolysis associated with Kir6.2 mutations (Albaqumi et al, 2014), and Flanagan et al (2017) recently reported a patient with persistent hyperinsulinaemic hypoglycaemia and severe hypotonia resulting from an activating mutation in a calcium channel subunit, which etiologically may have the same basis (Flanagan et al, 2017). Recently, we described a novel ABCC9-related Intellectual disability Myopathy Syndrome (AIMS) resulting from loss-offunction mutations in ABCC9 (SUR2) (Smeland et al, 2019), in which patients also exhibit muscular pain and fatigue, and evidence of muscle fiber damage.…”

Section: Discussion Katp Channels and Skeletal Musclementioning

confidence: 99%

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

et al. 2020

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Cantù syndrome (CS) arises from mutations in ABCC9 and KCNJ8 genes that lead to gain of function (GOF) of ATP-sensitive potassium (KATP) channels containing SUR2A and Kir6.1 subunits, respectively, of KATP channels. Pathological consequences of CS have been reported for cardiac and smooth muscle cells but consequences in skeletal muscle are unknown. Children with CS show muscle hypotonia and adult manifest fatigability. We analyzed muscle properties of Kir6.1[V65M] CS mice, by measurements of forelimb strength and ultrasonography of hind-limb muscles, as well as assessing KATP channel properties in native Flexor digitorum brevis (FDB) and Soleus (SOL) fibers by the patch-clamp technique in parallel with histopathological, immunohistochemical and Polymerase Chain Reaction (PCR) analysis. Forelimb strength was lower in Kir6.1wt/VM mice than in WT mice. Also, a significant enhancement of echodensity was observed in hind-limb muscles of Kir6.1wt/VM mice relative to WT, suggesting the presence of fibrous tissue. There was a higher KATP channel current amplitude in Kir6.1wt/VM FDB fibers relative to WT and a reduced response to glibenclamide. The IC50 of glibenclamide to block KATP channels in FDB fibers was 1.3 ± 0.2 × 10−7 M in WT and 1.2 ± 0.1 × 10−6 M in Kir6.1wt/VM mice, respectively; and it was 1.2 ± 0.4 × 10−7 M in SOL WT fibers but not measurable in Kir6.1wt/VM fibers. The sensitivity of the KATP channel to MgATP was not modified in Kir6.1wt/VM fibers. Histopathological/immunohistochemical analysis of SOL revealed degeneration plus regressive-necrotic lesions with regeneration, and up-regulation of Atrogin-1, MuRF1, and BNIP3 mRNA/proteins in Kir6.1wt/VM mice. Kir6.1wt/VM mutation in skeletal muscle leads to changes of the KATP channel response to glibenclamide in FDB and SOL fibers, and it is associated with histopathological and gene expression changes in slow-twitch muscle, suggesting marked atrophy and autophagy.

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Section: Discussion Katp Channels and Skeletal Musclementioning

confidence: 99%

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

et al. 2020

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“…ATP-dependent potassium channels take part in the regulation of insulin secretion through changes in the cell membrane potential of the β-cells. Mutations in the KCNJ11 gene lead to changes in the structure of the Kir6.2 channel and may lead to neonatal diabetes and congenital hyperinsulinemia (Albaqumi et al, 2014; Gohar et al, 2016). The rs5219 polymorphism in exon 1 of the KCNJ11 gene has been associated with the development of T2DM (Sakura et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Association of polymorphic markers of genes FTO, KCNJ11, CDKAL1, SLC30A8, and CDKN2B with type 2 diabetes mellitus in the Russian population

Никитин

Potapov²,

Brovkina

et al. 2017

PeerJ

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BackgroundThe association of type 2 diabetes mellitus (T2DM) with the KCNJ11, CDKAL1, SLC30A8, CDKN2B, and FTO genes in the Russian population has not been well studied. In this study, we analysed the population frequencies of polymorphic markers of these genes.MethodsThe study included 862 patients with T2DM and 443 control subjects of Russian origin. All subjects were genotyped for 10 single nucleotide polymorphisms (SNPs) of the genes using real-time PCR (TaqMan assays). HOMA-IR and HOMA-β were used to measure insulin resistance and β-cell secretory function, respectively.ResultsThe analysis of the frequency distribution of polymorphic markers for genes KCNJ11, CDKAL1, SLC30A8 and CDKN2B showed statistically significant associations with T2DM in the Russian population. The association between the FTO gene and T2DM was not statistically significant. The polymorphic markers rs5219 of the KCNJ11 gene, rs13266634 of the SLC30A8 gene, rs10811661 of the CDKN2B gene and rs9465871, rs7756992 and rs10946398 of the CDKAL1 gene showed a significant association with impaired glucose metabolism or impaired β-cell function.ConclusionIn the Russian population, genes, which affect insulin synthesis and secretion in the β-cells of the pancreas, play a central role in the development of T2DM.

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“…ATP-dependent potassium channels take part in the regulation of insulin secretion through changes in the cell membrane potential of the β-cells. Mutations in the KCNJ11 gene lead to changes in the structure of the Kir6.2 channel and may lead to neonatal diabetes and congenital hyperinsulinemia [7,8]. The rs5219 polymorphism in exon 1 of the KCNJ11 gene has been associated with the development of T2DM [9].…”

Section: Manuscript To Be Reviewedmentioning

confidence: 99%

Peer Review #1 of "Association of polymorphic markers of genes FTO, KCNJ11, CDKAL1, SLC30A8, and CDKN2B with type 2 diabetes mellitus in the Russian population (v0.2)"

2017

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Background. The association of type 2 diabetes mellitus (T2DM) with the KCNJ11, CDKAL1, SLC30A8, CDKN2B, and FTO genes in the Russian population has not been well studied. In this study, we analysed the population frequencies of polymorphic markers of these genes. Methods. The study included 862 patients with T2DM and 443 control subjects of Russian origin. All subjects were genotyped for 10 single nucleotide polymorphisms (SNPs) of the genes using real-time PCR (TaqMan assays). HOMA-IR and HOMA-β were used to measure insulin resistance and β-cell secretory function, respectively. Results. The analysis of the frequency distribution of polymorphic markers for genes KCNJ11, CDKAL1, SLC30A8 and CDKN2B showed statistically significant associations with T2DM in the Russian population. The association between the FTO gene and T2DM was not statistically significant. The polymorphic markers rs5219 of the KCNJ11 gene, rs13266634 of the SLC30A8 gene, rs10811661 of the CDKN2B gene and rs9465871, rs7756992 and rs10946398 of the CDKAL1 gene showed a significant association with impaired glucose metabolism or impaired β-cell function. Conclusion. In the Russian population, genes, which affect insulin synthesis and secretion in the β-cells of the pancreas, play a central role in the development of T2DM.

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A syndrome of congenital hyperinsulinism and rhabdomyolysis is caused byKCNJ11mutation

Abstract: This study expands the phenotype associated with KCNJ11 loss of function in humans and calls for increased awareness of rhabdomyolysis as a potential late-onset life-threatening complication of KCNJ11-related congenital hyperinsulinism.

Cited by 7 publications

References 20 publications

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

Association of polymorphic markers of genes FTO, KCNJ11, CDKAL1, SLC30A8, and CDKN2B with type 2 diabetes mellitus in the Russian population

Peer Review #1 of "Association of polymorphic markers of genes FTO, KCNJ11, CDKAL1, SLC30A8, and CDKN2B with type 2 diabetes mellitus in the Russian population (v0.2)"

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