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Titolo:
Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy - Nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1
Autore:
Tanizawa, Y; Matsuda, K; Matsuo, M; Ohta, Y; Ochi, N; Adachi, M; Koga, M; Mizuno, S; Kajita, M; Tanaka, Y; Tachibana, K; Inoue, H; Furukawa, S; Amachi, T; Ueda, K; Oka, Y;
Indirizzi:
Yamaguchi Univ, Sch Med, Dept Internal Med 3, Yamaguchi 7559505, Japan Yamaguchi Univ Yamaguchi Japan 7559505 l Med 3, Yamaguchi 7559505, Japan Yamaguchi Univ, Sch Med, Dept Pediat, Yamaguchi 7559505, Japan Yamaguchi Univ Yamaguchi Japan 7559505 Pediat, Yamaguchi 7559505, Japan Kyoto Univ, Grad Sch Agr, Biochem Lab, Kyoto, Japan Kyoto Univ Kyoto Japan to Univ, Grad Sch Agr, Biochem Lab, Kyoto, Japan Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Kyoto, Japan Kyoto Univ Kyoto Japan v, Grad Sch Agr, Div Appl Life Sci, Kyoto, Japan Aichi Prefectural Hosp, Kasugai, Aichi, Japan Aichi Prefectural Hosp Kasugai Aichi Japan l Hosp, Kasugai, Aichi, Japan Habilitat Ctr Disabled Children, Daini Aoitori Gakuen, Japan Habilitat CtrDisabled Children Daini Aoitori Gakuen Japan akuen, Japan Kanagawa Childrens Med Ctr, Dept Endocrinol & Metab, Kanagawa, Japan Kanagawa Childrens Med Ctr Kanagawa Japan inol & Metab, Kanagawa, Japan Kanagawa Childrens Med Ctr, Div Pathol, Kanagawa, Japan Kanagawa ChildrensMed Ctr Kanagawa Japan , Div Pathol, Kanagawa, Japan Tokai Municipal Hosp, Dept Pediat, Tokai, Ibaraki, Japan Tokai Municipal Hosp Tokai Ibaraki Japan t Pediat, Tokai, Ibaraki, Japan Nagoya Univ, Sch Med, Dept Pediat, Nagoya, Aichi 466, Japan Nagoya Univ Nagoya Aichi Japan 466 Dept Pediat, Nagoya, Aichi 466, Japan
Titolo Testata:
DIABETES
fascicolo: 1, volume: 49, anno: 2000,
pagine: 114 - 120
SICI:
0012-1797(200001)49:1<114:GAOJPW>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
FOCAL ADENOMATOUS HYPERPLASIA; PANCREATIC BETA-CELLS; K-ATP CHANNEL; FAMILIAL HYPERINSULINISM; INSULIN-SECRETION; INTRACELLULAR ATP; SEQUENCE VARIANTS; KIR6.2; NIDDM; SUBUNIT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
34
Recensione:
Indirizzi per estratti:
Indirizzo: Tanizawa, Y Yamaguchi Univ, Sch Med, Dept Internal Med 3, 1-1-1 Minami Kogushi, Yamaguchi 7559505, Japan Yamaguchi Univ 1-1-1 Minami Kogushi Yamaguchi Japan 7559505 n
Citazione:
Y. Tanizawa et al., "Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy - Nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1", DIABETES, 49(1), 2000, pp. 114-120

Abstract

To elucidate the genetic etiology of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) in the Japanese population, we conducted a polymerasechain reaction-single-strand conformation polymorphism analysis of the sulfonylurea receptor 1 (SUR1) and Kir6.2 genes in 17 Japanese PHHI patients, including a pair of siblings from a consanguineous family. me also analyzedthe glutamate dehydrogenase gene for the exons encoding an allosteric regulatory domain of the enzyme. In the SUR1 gene, we identified one frameshift(I446fsdelT) and two missense (R1420C, R1436Q) mutations. None of these mutations mere found in control Japanese subjects. Siblings homozygous for the R1420C mutation had a mild form, whereas two patients heterozygous for the I446fsdelT and R1436Q mutations, respectively, exhibited a severe form ofPHHI. Functional consequences of these mutations on K-ATP function mere evaluated using Rb-86(+) efflux studies in COS-7 cells. SUR1-446fsdelT and SUR1-1436Q did not form a functional K-ATP. Western blot analysis after transient expression in COS-7 cells revealed the expression of SUR1-1436Q protein to be markedly reduced, suggesting SUR1-1436Q to be unstable in these cells. K-ATP (SUR1-1420C) showed reduced responses to metabolic inhibition by oligomycin and 2-deoxyglucose. K-ATP channels are under complex regulation by intracellular ATP and ADP. ATP both inhibits and activates these channels. The inhibition is probably mediated through direct ATP interaction with a pore-forming subunit Kir6.2, whereas the activation is likely to be through a regulatory subunit SUR1. There is a cooperative regulation of ATP and ADP binding to SUR1, and this cooperativity may be involved in regulating the K-ATP channel. In SUR1-1420C, high-affinity binding of ATP to the nucleotide-binding fold (NBF)-1 was indistinguishable from that of wild-type SUR1. However, stabilization of ATP binding to NBF-1 by MgATP or MgADP mas impaired, suggesting that this defect may account for impaired K-ATP(SUR1-1420C) function. This is the first direct biochemical evidence that the cooperativity of nucleotide binding to SUR1 is impaired in a SUR1 mutant causing PHHI. No mutations mere identified in the Kir6.2 and glutamate dehydrogenase genes. The genetic etiology of PHHI appears to be heterogeneous. SUR1 mutations may account for no more than 20% of PHHI cases in Japanese patients. Mutations of Kir6.2 and glutamate dehydrogenase genes are likely to be even less common.

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Documento generato il 07/07/20 alle ore 11:21:10