Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype

Flanagan, Sarah E.; Edghill, Emma L.; Gloyn, Anna L.; Ellard, Sian; Hattersley, Andrew T.

doi:10.1007/s00125-006-0246-z

Cited by 206 publications

(188 citation statements)

References 25 publications

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“…Genomic DNA was extracted from peripheral leukocytes using standard procedures. The single exon of KCNJ11 was amplified by PCR as previously described (15). When no mutations were identified, the 39 exons of the ABCC8 gene encoding the SUR1 protein were amplified using previously described primers (16).…”

Section: Methodsmentioning

confidence: 99%

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

et al. 2008

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OBJECTIVE-Congenital hyperinsulinism (CHI) may be due to diffuse or focal pancreatic disease. The diffuse form is associated with an increase in the size of ␤-cell nuclei throughout the whole of the pancreas and most commonly results from recessive ATP-sensitive K ϩ channel (K ATP channel) mutations. Focal lesions are the consequence of somatic uniparental disomy for a paternally inherited K ATP channel mutation with enlargement of the ␤-cell nuclei confined to the focal lesion. Some "atypical" cases defy classification and show pancreatic ␤-cell nuclear enlargement confined to discrete regions of the pancreas. We investigated an atypical case with normal morphology within the tail of the pancreas but occasional enlarged endocrine nuclei in parts of the body and head. RESEARCH DESIGN AND METHODS-The KCNJ11 andABCC8 genes encoding the K ATP channel subunits and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and her parents.RESULTS-A mosaic ABCC8 nonsense mutation (Q54X) was identified in the proband. The paternally inherited mutation was present at 90% in lymphocytes and 50% in normal pancreatic sections but between 64 and 74% in abnormal sections. Microsatellite analysis showed mosaic interstitial paternal uniparental isodisomy (UPD) for chromosome 11p15.1.CONCLUSIONS-We report a novel genetic mechanism to explain atypical histological diffuse forms of CHI due to mosaic UPD in patients with dominantly inherited ABCC8 (or KCNJ11) gene mutations.

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Section: Methodsmentioning

confidence: 99%

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

et al. 2008

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“…In addition, phenotypic variability associated with different mutations at the same residues has been reported. For example, a substitution of glutamine for arginine at codon 50 (R50Q) causes TNDM whereas a substitution to proline at the same residue (R50P) causes PNDM (17,19). A second example is seen with mutations affecting codon 53 where a substitution of glycine to asparagine (G53N) causes isolated diabetes while a substitution to an aspartic acid at the same residue (G53D) results in DEND syndrome (19,20,21).…”

Section: Introductionmentioning

confidence: 99%

Amino acid properties may be useful in predicting clinical outcome in patients with Kir6.2 neonatal diabetes

Fraser

Rubio-Cabezas

Littlechild

et al. 2012

European Journal of Endocrinology

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Background: Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the b-cell K ATP channel, are a common cause of neonatal diabetes. The diabetes may be permanent neonatal diabetes mellitus (PNDM) or transient neonatal diabetes mellitus (TNDM), and in w20% of patients, neurological features are observed. A correlation between the position of the mutation in the protein and the clinical phenotype has previously been described; however, recently, this association has become less distinct with different mutations at the same residues now reported in patients with different diabetic and/or neurological phenotypes. Methods: We identified from the literature, and our unpublished series, KCNJ11 mutations that affected residues harbouring various amino acid substitutions (AAS) causing differences in diabetic or neurological status. Using the Grantham amino acid scoring system, we investigated whether the difference in properties between the wild-type and the different AAS at the same residue could predict phenotypic severity. Results: Pair-wise analysis demonstrated higher Grantham scores for mutations causing PNDM or diabetes with neurological features when compared with mutations affecting the same residue that causes TNDM (PZ0.013) or diabetes without neurological features (PZ0.016) respectively. In just five of the 25 pair-wise analyses, a lower Grantham score was observed for the more severe phenotype. In each case, the wild-type residue was glycine, the simplest amino acid. Conclusion: This study demonstrates the importance of the specific AAS in determining phenotype and highlights the potential utility of the Grantham score for predicting phenotypic severity for novel KCNJ11 mutations affecting previously mutated residues.

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“…In addition, mutations in other genes (IPF1, PTF1A, FOXP3, GLIS3, TCF2, EIF2AK3) can lead to multisystem diseases that include ND (2). As a result of genetic studies, the view has emerged that ND is primarily a genetic disorder and not a congenital form of type 1 diabetes with a cutoff at around 6 months (8,9). Spontaneous mutations are common in ND with 80% of the mutations in KCNJ11 (the gene encoding Kir6.2) occurring de novo (10).…”

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confidence: 99%

Insulin gene mutations as a cause of permanent neonatal diabetes

Støy

Edghill

Flanagan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

511

478

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We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with ␤ cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially ␤ cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of ␤ cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.endoplasmic reticulum stress ͉ insulin biosynthesis ͉ disulfide bonds ͉ unfolded protein response

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Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype

Cited by 206 publications

References 25 publications

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

Amino acid properties may be useful in predicting clinical outcome in patients with Kir6.2 neonatal diabetes

Insulin gene mutations as a cause of permanent neonatal diabetes

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