Permanent neonatal diabetes in an Asian infant

Porter, J. R.; Shaw, Nick; Barrett, Timothy; Hattersley, Andrew T.; Ellard, Sian; Gloyn, Anna L.

doi:10.1016/j.jpeds.2004.09.008

Cited by 51 publications

(38 citation statements)

References 11 publications

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“…These mutations include three novel ones: the insertion of an asparagine residue at position 161 (inserN161) and two missense mutations, R308W and M235V; we also report a fourth missense mutation, R397L, which has been reported previously [20]. Functional analysis of these mutations was carried out by measuring their effects on the kinetic parameters of the enzyme, on protein stability, and on the interaction of GCK with the associated proteins GCKR, PFKFB1 and dual specificity phosphatase 12 (DUSP12).…”

Section: Introductionsupporting

confidence: 69%

“…Mutation R397L was previously identified in an Asian infant with permanent neonatal diabetes [20]. This child had a milder phenotype than other permanent neonatal diabetes-GCK patients, suggesting to those authors that this mutation may cause a less severe kinetic defect than the previously reported mutations.…”

Section: Discussionmentioning

confidence: 69%

“…Three of these mutations are novel (inserN161, M235V and R308W), and one (R397L) had been identified previously in an Asian infant with permanent neonatal diabetes mellitus [20]. The novel mutations inserN161, M235V and R308W cosegregated with diabetes or impaired glucose tolerance in their respective families and were not found in over 100 chromosomes from non-diabetic control subjects.…”

Section: Discussionmentioning

confidence: 89%

“…Point mutations in GCK exons 8 and 7 resulted in novel missense GCK mutations R308W and M235V, found in families P35 and P42, respectively. The missense mutation R397L, found in family P38, was first reported as a homozygous mutation in an Asian infant with permanent neonatal diabetes [20]. The three novel mutations co-segregated with the MODY phenotype in the available subjects in their respective families (Table 1), and were not found in 55 unrelated healthy control individuals, who showed normal conformers of SSCP compared with the probands and their affected relatives (results not shown).…”

Section: Identification Of Novel Mody2 Mutationsmentioning

confidence: 91%

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Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

et al. 2006

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Aims/hypothesis Glucokinase (GCK) acts as a glucose sensor in the pancreatic beta cell and regulates insulin secretion. In the gene encoding GCK the heterozygous mutations that result in enzyme inactivation cause MODY2. Functional studies of naturally occurring GCK mutations associated with hyperglycaemia provide further insight into the biochemical basis of glucose sensor regulation. Materials and methods Identification of GCK mutations in selected MODY patients was performed by single-strand conformation polymorphism and direct sequencing. The kinetic parameters and thermal stability of recombinant mutant human GCK were determined, and in pull-down assays the effect of these mutations on the association of GCK with glucokinase (hexokinase 4) regulator (GCKR, also known as glucokinase regulatory protein [GKRP]) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1, also known as PFK2) was tested. Results We identified three novel GCK mutations: the insertion of an asparagine residue at position 161 (inserN161) and two missense mutations (M235V and R308W). We also identified a fourth mutation (R397L) reported in a previous work. Functional characterisation of these mutations revealed that insertion of asparagine residue N161 fully inactivates GCK, whereas the M235V and R308W mutations only partially impair enzymatic activity. In contrast, GCK kinetics was almost unaffected by the R397L mutation. Although none of these mutations affected the interaction of GCK with PFKFB1, we found that the R308W mutation caused protein instability and increased the strength of interaction with GCKR. Conclusions/interpretation Our results show that different MODY2 mutations impair GCK function through different mechanisms such as enzymatic activity, protein stability and increased interaction with GCKR, helping further elucidate the regulation of GCK activity.

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Section: Introductionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 89%

Section: Identification Of Novel Mody2 Mutationsmentioning

confidence: 91%

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Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

et al. 2006

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“…Unique kinetic characteristics are low affinity for the substrate glucose (S 0.5 ϳ7.5 mmol/l) at pH 7.4, physiological saturation with MgATP, cooperativity with its substrate glucose (Hill coefficient n H ϳ1. 7), and lack of inhibition by intermediates and products of the glycolytic pathway. These are important features that allow glucokinase to serve a special function in the glucose sensing of several tissues including pancreas (␤-and ␣-cells), hepatoportal, L-and K-type enteroendocrine cells, and certain neurons mainly in the hypothalamus (1)(2)(3).…”

mentioning

confidence: 99%

From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation

Sagen

Odili²,

Bjørkhaug³

et al. 2006

Diabetes

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Glucokinase functions as a glucose sensor in pancreatic ␤-cells and regulates hepatic glucose metabolism. A total of 83 probands were referred for a diagnostic screening of mutations in the glucokinase (GCK) gene. We found 11 different mutations (V62A, G72R, L146R, A208T, M210K, Y215X, S263P, E339G, R377C, S453L, and IVS5 ؉ 1G>C) in 14 probands. Functional characterization of recombinant glutathionyl S-transferase-G72R glucokinase showed slightly increased activity, whereas S263P and G264S had near-normal activity. The other point mutations were inactivating. S263P showed marked thermal instability, whereas the stability of G72R and G264S differed only slightly from that of wild type. G72R and M210K did not respond to an allosteric glucokinase activator (GKA) or the hepatic glucokinase regulatory protein (GKRP). Mutation analysis of the role of glycine at position 72 by substituting E, F, K, M, S, or Q showed that G is unique since all these mutants had very low or no activity and were refractory to GKRP and GKA. Structural analysis provided plausible explanations for the drug resistance of G72R and M210K. Our study provides further evidence that protein instability in combination with loss of control by a putative endogenous activator and GKRP could be involved in the development of hyperglycemia in maturity-onset diabetes of the young, type 2. Furthermore, based on data obtained on G264S, we propose that other and still unknown mechanisms participate in the regulation of glucokinase.

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