Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet

Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, USA.
Human Molecular Genetics (Impact Factor: 6.39). 04/2005; 14(7):925-34. DOI: 10.1093/hmg/ddi086
Source: PubMed


Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM). Mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium channel (K(ATP)), are the commonest cause of permanent neonatal diabetes (PNDM). In addition to diabetes, some KCNJ11 mutations also result in marked developmental delay and epilepsy. These mutations are more severe on functional characterization. We investigated whether mutations in KCNJ11 could also give rise to TNDM. We identified the three novel heterozygous mutations (G53S, G53R, I182V) in three of 11 probands with clinically defined TNDM, who did not have chromosome 6q24 abnormalities. The mutations co-segregated with diabetes within families and were not found in 100 controls. All probands had insulin-treated diabetes diagnosed in the first 4 months and went into remission by 7-14 months. Functional characterization of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes. All three heterozygous mutations resulted in a reduction in the sensitivity to ATP when compared with wild-type (IC(50) approximately 30 versus approximately 7 microM, P-value for is all <0.01); however, this was less profoundly reduced than with the PNDM associated mutations. In conclusion, mutations in KCNJ11 are the first genetic cause for remitting as well as permanent diabetes. This suggests that a fixed ion channel abnormality can result in a fluctuating glycaemic phenotype. The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro.


Available from: Peter Proks
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    • "Thus the three novel mutations identified were R177G, C344R and V138L. Common polymorphism observed in Kir6.2 gene was E23K and reported in many studies [11] [17] [18] [19] [20] [21] [22] [23] [24]. But this mutation was not observed in our study. "
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    ABSTRACT: Targeted genomic studies are required to understand complex polygenic disorders such as Diabetes. In this context our approach was to detect the polymorphism in ATP-sensitive potassium (KATP) channel protein subunit Kir6.2. Blood samples of normal and type2 diabetic patients in and around the Chittoor district were obtained. Amplification of Kir6.2 gene was done by custom designed primers from genomic DNA of normal and type2 diabetic patients and amplification products were sent for sequencing. Three mutations i.e., R177G, C344R, V138L corresponding to the region of Kir6.2 has been identified in comparative analysis. The crystal structure of Kir6.2 protein model is not available so far in any database and hence we modeled the structure using Modeller software tool and validated the stereo chemical quality of modeled structure by using PROCHECK and ProsaWeb model. Mutated conformations were generated after the introduction of the R177G, C344R and V138L mutations and subsequent energy minimization and molecular dynamics were done. RMSDs were observed to be 5.406 Å, 5.123 Å and 5.449 Å for R177G, V138L and C344R mutated structures respectively and these conformational and RMSD variations were observed to affect the functionality of the K ATP sensitive channels there by leads to increased glucose levels.
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    • "Activating mutations in either the KCNJ11 or ABCC8 genes encoding the two subunits (Kir6.2 and SUR1, respectively) of the ATP-sensitive potassium (KATP) channel of the β-cell membrane, prevent insulin secretion in response to hyperglycaemia and can cause both PNDM and TNDM [26,27,28]. KCNJ11 mutations are more frequent, and most patients have PNDM rather than TNDM. "
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    ABSTRACT: Over the last decade, we have witnessed major advances in the understanding of the molecular basis of neonatal and infancy-onset diabetes. It is now widely accepted that diabetes presenting before 6 months of age is unlikely to be autoimmune type 1 diabetes. The vast majority of such patients will have a monogenic disorder responsible for the disease and, in some of them, also for a number of other associated extrapancreatic clinical features. Reaching a molecular diagnosis will have immediate clinical consequences for about half of affected patients, as identification of a mutation in either of the two genes encoding the ATP-sensitive potassium channel allows switching from insulin injections to oral sulphonylureas. It also facilitates genetic counselling within the affected families and predicts clinical prognosis. Importantly, monogenic diabetes seems not to be limited to the first 6 months but extends to some extent into the second half of the first year of life, when type 1 diabetes is the more common cause of diabetes. From a scientific perspective, the identification of novel genetic aetiologies has provided important new knowledge regarding the development and function of the human pancreas.
    Hormone Research in Paediatrics 09/2013; 80(3):137-146. DOI:10.1159/000354219 · 1.57 Impact Factor
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    • "Most of remaining cases are caused by mutations in either KCNJ11 or ABCC8 genes that encode the ATP-sensitive potassium (KATP) channel respectively [2]. The precise mechanism of TNDM is unknown; it has been proposed that it could be due to either a reduced insulin requirement at the time of remission or because of some compensation effects at the level of the β-cell, pancreas, or whole body [3]. "
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    ABSTRACT: Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in pancreatic β-cells play a crucial role in insulin secretion and glucose homeostasis. These channels are composed of two subunits: a pore-forming subunit (Kir6.2) and a regulatory subunit (sulphonylurea receptor-1). Recent studies identified large number of gain of function mutations in the regulatory subunit of the channel which cause neonatal diabetes. Majority of mutations cause neonatal diabetes alone, however some lead to a severe form of neonatal diabetes with associated neurological complications. This review focuses on the functional effects of these mutations as well as the implications for treatment.
    Diabetes & metabolism journal 06/2013; 37(3):157-164. DOI:10.4093/dmj.2013.37.3.157
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