Family with autosomal dominant hyperinsulinism associated with A456V mutation in the glucokinase gene

Dullaart, Rpf; Hoogenberg, Klaas; Rouwé, C.W.; Stulp, Ben K.

doi:10.1046/j.0954-6820.2003.01243.x

Cited by 18 publications

(16 citation statements)

References 7 publications

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“…Including this report, only seven mutations in nine families have been described, in contrast to over 200 inactivating GCK mutations causing the opposite phenotype, GCK-MODY (10,18,(21)(22)(23)(24)31). In the present study, we have identified a seventh, naturally occurring activating GCK mutation (S64Y), and have functionally characterised the mutant enzyme.…”

Section: Discussionmentioning

confidence: 96%

“…However, other functionally proven mutations (T65I, W99R and A456V) were predicted to be benign with PSIC scores of 0.187, 0.192 and 1.252 respectively. With the addition of our novel mutation, the known naturally occurring activating GCK mutations mapping to the allosteric site are: S64Y, T65I, G68V, W99R, Y214C, V455M and A456V (10,18,(21)(22)(23)(24). In addition, the GCK-MODY V62M mutation has been shown to be kinetically activating in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, polyubiquitin chains have been suggested to be endogenous ligands for this domain of the enzyme (20). A total of six mutations have been described in seven families with GCK-CHI (10,18,(21)(22)(23)(24) indicating that the prevalence is low. However, GCK has not been investigated systematically in large series of CHI cases.…”

Section: Introductionmentioning

confidence: 99%

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Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation.

Christesen

Tribble

Molven

et al. 2008

European Journal of Endocrinology

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Objective: Activating glucokinase (GCK) mutations are a rarely reported cause of congenital hyperinsulinism (CHI), but the prevalence of GCK mutations is not known. Methods: From a pooled cohort of 201 non-syndromic children with CHI from three European referral centres (Denmark, nZ141; Norway, nZ26; UK, nZ34), 108 children had no K ATP -channel (ABCC8/KCNJ11) gene abnormalities and were screened for GCK mutations. Novel GCK mutations were kinetically characterised. Results: In five patients, four heterozygous GCK mutations (S64Y, T65I, W99R and A456V) were identified, out of which S64Y was novel. Two of the mutations arose de novo, three were dominantly inherited. All the five patients were medically responsive. In the combined Danish and Norwegian cohort, the prevalence of GCK-CHI was estimated to be 1.2% (2/167, 95% confidence interval (CI) 0-2.8%) of all the CHI patients. In the three centre combined cohort of 72 medically responsive children without K ATP -channel mutations, the prevalence estimate was 6.9% (5/72, 95% CI 1.1-12.8%). All activating GCK mutations mapped to the allosteric activator site. The novel S64Y mutation resulted in an increased affinity for the substrate glucose (S 0.5 1.49G0.08 and 7.39G0.05 mmol/l in mutant and wild-type proteins respectively), extrapolating to a relative activity index of w22 compared with the wild type. Conclusion: In the largest study performed to date on GCK in children with CHI, GCK mutations were found only in medically responsive children who were negative for ABCC8 and KCNJ11 mutations. The estimated prevalence (w7%) suggests that screening for activating GCK mutations is warranted in those patients.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation.

Christesen

Tribble

Molven

et al. 2008

European Journal of Endocrinology

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“…There are only seven activating GCK mutations described and found in six families and one individual (8-12,18) ( Table 2). The clinical phenotype of this type of monogenic hyperinsulinism turned out to be highly heterogeneous, resulting in both mild and severe forms (8)(9)(10)(11)(12)18). …”

Section: Discussionmentioning

confidence: 99%

Diagnostic Difficulties in Glucokinase Hyperinsulinism

Meißner¹,

Marquard²,

Cobo-Vuilleumier³

et al. 2008

Horm Metab Res

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“…A ativação dessa enzima aumenta a oxidação de glutamato e aumenta a relação ATP/ADP na célula B. As mutações ativadoras de GCK (7p15-p13) reduzem o limite da secreção de insulina estimulada pela glicose (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41).…”

Section: Glud1 E Gckunclassified

Hipoglicemia hiperinsulinêmica da infância

Liberatore

Martinelli

2011

Arq Bras Endocrinol Metab

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SUMÁRIOA hipoglicemia hiperinsulinêmica da infância (HHI) é uma emergência no período neonatal. Após curtos períodos de jejum, o cérebro ávido por glicose corre o risco de ficar sem seu principal substrato energético. Os critérios de diagnóstico de HH, tanto no período neonatal quanto na criança maior e na adolescência, foram revisados. Foram descritas as etiologias e a fisiopatologia da HHI. As alterações moleculares frequentemente encontradas, bem como a descrição das principais mutações, são abordadas. Arq Bras Endocrinol Metab. 2011;55(3):177-83 Descritores Hipoglicemia; insulina; hiperinsulinismo SUMMARYThe hypoglycemia hyperinsulinemic of the infancy (HHI) is an emergency in the neonatal period. After a short period of fast the avid brain runs out of its main energy substrate. The authors overhaul the diagnosis of HH, not only in the neonatal period, but also in the late infant and in the adolescence. The aspects of the molecular alterations found in these cases, as well like the description of the main mutations are also approached. Nesses períodos, o tecido cerebral ainda não completamente maduro, marcado por intensa atividade metabólica e extremamente ávido por glicose, torna-se bastante sensível às reduções de níveis glicêmicos mesmo que fugazes.Dessa forma, a ocorrência de episódios repetidos de hipoglicemia nessa fase da vida pode trazer danos cerebrais, na maioria das vezes graves e irreversíveis (1-4).A secreção inapropriadamente aumentada de insulina, sem relação com os níveis de glicemia, caracteriza hiperinsulinemia, que é a principal causa de hipoglicemia persistente e recorrente nessa fase da vida (1,5,6).Essa situação clínica é marcada pelo aumento da utilização da glicose pelos tecidos sensíveis às ações da insulina, ao mesmo tempo que o aumento da concentração de insulina inibe a produção endógena de glicose, bloqueando a glicólise e a neoglicogênese. Em decorrência desse bloqueio, não ocorre produção de corpos cetônicos, substrato energético alternativo para o tecido cerebral (6).A queda acentuada dos níveis glicêmicos e a falta de produção de corpos cetônicos são as causas dos danos cerebrais frequentemente associados a essa condição clí-nica. O cérebro em desenvolvimento ávido por combustível não tem como utilizar nenhuma fonte energética. Assim, essa situação clínica se transforma em uma das emergências do período neonatal.A identificação precoce e a correta abordagem da hipoglicemia hiperinsulinêmica (HH) são, dessa forma, de extrema importância para reduzir a morbi-mortalidade dessa patologia. ETIOLOGIASVárias são as causas da HH. Essas podem ser congênitas, secundárias, associadas a síndromes genéticas ou associadas a doenças metabólicas (1,3,6).

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Family with autosomal dominant hyperinsulinism associated with A456V mutation in the glucokinase gene

Cited by 18 publications

References 7 publications

Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation.

Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation.

Diagnostic Difficulties in Glucokinase Hyperinsulinism

Hipoglicemia hiperinsulinêmica da infância

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