Activating Mutations in the<i>ABCC8</i>Gene in Neonatal Diabetes Mellitus

Babenko, Andrey P.; Polak, Michel; Cavé, Hélène; Busiah, Kanetee; Czernichow, P; Scharfmann, Raphaël; Bryan, Joseph; Aguilar‐Bryan, Lydia; Vaxillaire, Martine; Froguel, Philippe

doi:10.1056/nejmoa055068

Cited by 597 publications

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“…H1023Y in TM12, Babenko et al 2006;L225P in CL3, Masia et al 2007) enhance Mg-nucleotide activation by unknown mechanisms. Such naturally occurring mutations provide fresh insights into K ATP channel function and are especially valuable when structural information is lacking.…”

Section: When Regulation Fails: Sur1 Mutations and Diseasementioning

confidence: 99%

“…The R1380L mutation seems to speed up the catalytic cycle, so that the protein spends less time in the pre-hydrolytic ATP-bound state (de Wet et al 2007b). The I1425V mutation in NBD2 also shows greater Mg-nucleotide-dependent stimulation of the channel activity (Babenko et al 2006;I1424V in their notation). While other NBD mutations have not been analysed in detail, their location suggests that they may also influence ATPase activity and/or Mg-nucleotide activation.…”

Section: When Regulation Fails: Sur1 Mutations and Diseasementioning

confidence: 99%

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SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

Aittoniemi

Fotinou

Craig

et al. 2008

Phil. Trans. R. Soc. B

147

132

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SUR1 is an ATP-binding cassette (ABC) transporter with a novel function. In contrast to other ABC proteins, it serves as the regulatory subunit of an ion channel. The ATP-sensitive (K ATP ) channel is an octameric complex of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits, and it links cell metabolism to electrical activity in many cell types. ATPase activity at the nucleotidebinding domains of SUR results in an increase in K ATP channel open probability. Conversely, ATP binding to Kir6.2 closes the channel. Metabolic regulation is achieved by the balance between these two opposing effects. Precisely how SUR1 talks to Kir6.2 remains unclear, but recent studies have identified some residues and domains that are involved in both physical and functional interactions between the two proteins. The importance of these interactions is exemplified by the fact that impaired regulation of Kir6.2 by SUR1 results in human disease, with loss-of-function SUR1 mutations causing congenital hyperinsulinism and gain-of-function SUR1 mutations leading to neonatal diabetes. This paper reviews recent data on the regulation of Kir6.2 by SUR1 and considers the molecular mechanisms by which SUR1 mutations produce disease.

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Section: When Regulation Fails: Sur1 Mutations and Diseasementioning

confidence: 99%

Section: When Regulation Fails: Sur1 Mutations and Diseasementioning

confidence: 99%

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

Aittoniemi

Fotinou

Craig

et al. 2008

Phil. Trans. R. Soc. B

147

132

View full text Add to dashboard Cite

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“…In diabetes, the cleanest example is provided by neonatal diabetes caused by activating mutations in the genes that encode the sulfonylurea receptor (ABCC8) or its associated ATP-dependent potassium channel (KCNJ11), which lie adjacent to each other in chromosome 11. Constitutively activating mutations that lead to hyperactivity of this complex impair the ability of beta cells to depolarise in response to a glucose stimulus, hindering insulin secretion and causing insulin insufficiency [5,6]. The resulting hyperglycaemia is typically detected in the first year of life and must be distinguished from the autoimmune destruction of pancreatic beta cells that occurs in type 1 diabetes.…”

Section: Target Identificationmentioning

confidence: 99%

“…Though very early onset (<6 months) and the absence of autoantibodies favour the diagnosis of neonatal diabetes, genetic confirmation is typically required [7]. In many of these cases, the genetic defect can be overcome by high doses of the very same medication class (sulfonylureas) that targets the sulfonylurea receptor/potassium channel complex [6,8]. Patients with documented mutations in the relevant genes can be safely transitioned to an oral regimen and shed multiple daily insulin injections; their sustained improvement in glycaemic response demonstrates that the use of pharmacogenetic information in patient care can improve not only the quality of care but also the quality of life.…”

Section: Target Identificationmentioning

confidence: 99%

Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool?

Florez

2017

Diabetologia

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“…A cetoacidose é mais rara, mas poderá acontecer se a insulinoterapia não for iniciada. Esta forma rara de DM dependente de insulina manifesta-se já no primeiro mês de vida e está associada a doenças monogênicas raras, podendo ter uma evolução transitória, transitória e recorrente (em geral na adolescência), ou pode ser permanente 7,8 .…”

Section: Outras Formas De Diabetes Melito Na Infância E Adolescênciaunclassified

Not every diabetic child has type 1 diabetes mellitus

Manna¹

2007

J Pediatr (Rio J)

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Objetivo: Apesar de o diabetes melito tipo 1 de origem autoimune ser o mais prevalente na infância e adolescência, outras formas de diabetes também podem acometer essa população, implicando em prognóstico e tratamentos diferentes. Fontes dos dados:Foram utilizadas informações através de revisão bibliográfica realizada por busca direta de artigos científicos nas bases de dados MEDLINE e LILACS, além de publicações clássicas referentes ao tema, sendo escolhidas as mais representativas. Síntese dos dados:Este artigo discute os mecanismos fisiopatológicos, quadro clínico e tratamento das diversas formas de diabetes que acometem a faixa etária pediátrica, como diabetes melito tipo 1, diabetes melito tipo 2, diabetes do tipo maturity-onset diabetes of youth, diabetes neonatal, diabetes mitocondrial, diabetes da lipodistrofia generalizada, diabetes secundário a outras pancreatopatias, diabetes secundário a outras endocrinopatias, diabetes associado a infecções e drogas citotóxicas e diabetes relacionado a algumas síndromes genéticas. Conclusão:O reconhecimento do mecanismo fisiopatológico primário da forma de diabetes apresentada pode orientar seu tratamento específico, otimizando seu controle metabólico e minimizando suas complicações a longo prazo. J Pediatr (Rio J). 2007;83(5 Supl):S178-183:Diabetes melito, diagnóstico diferencial, criança, diabetes melito neonatal, síndromes.Objective: Although it is type 1 diabetes mellitus of autoimmune origin that is most prevalent in childhood and adolescence, other forms of diabetes can also affect this population, resulting in different prognosis and treatment.Sources: Information was obtained by means of a bibliographic review, carried out by running searches for scientific articles in the MEDLINE and LILACS databases, in addition to classic publications on the subject, with the most representative being chosen. Summary of the findings:This article discusses the pathophysiological mechanisms, clinical presentation and treatment of the various forms of diabetes that affect the pediatric age group, such as type 1 diabetes mellitus, type 2 diabetes mellitus, maturity-onset diabetes of youth, neonatal diabetes, mitochondrial diabetes, diabetes of generalized lipodystrophy, diabetes secondary to other pancreatic diseases, diabetes secondary to other endocrine diseases, diabetes associated with infections and cytotoxic drugs and diabetes related to certain genetic syndromes. Conclusions:Recognition of the primary pathophysiologic mechanism of the form of diabetes presented can guide specific treatment, optimizing metabolic control and minimizing complications over the long term. J Pediatr (Rio J). 2007;83(5 Suppl):S178-183:Diabetes mellitus, differential diagnosis, child, diabetes mellitus neonatal, syndromes. IntroduçãoO diabetes melito (DM) é uma doença metabólica de etiologia múltipla. É caracterizado pela hiperglicemia crônica resultante de distúrbios no metabolismo de carboidratos, proteínas e gorduras, em função de secreção insuficiente e/ou ausente de insulina, como também ...

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Activating Mutations in theABCC8Gene in Neonatal Diabetes Mellitus

Cited by 597 publications

References 32 publications

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool?

Not every diabetic child has type 1 diabetes mellitus

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