Genotypes of the pancreatic β-cell K-ATP channel and clinical pnenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy

Kumiko Ohkubo, Mariko Nagashima, Yuko Naito, Tomoaki Taguchi, Sachiyo Suita, Nobuhiko Okamoto, Hideshi Fujinaga, Kumi Tsumura, Kiyoshi Kikuchi, Junko Ono

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Abstract

Objective: Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a disorder of glucose metabolism that is characterized by dysregulated secretion of insulin from pancreatic β-cells. This disease has been reported to be associated with mutations of the sulfonylurea receptor SUR1 (ABCC8) or the inward-rectifying potassium channel Kir6.2 (KCNJ11), which are two subunits of the pancreatic β-cell ATP-sensitive potassium channel. Patients and Methods: In 14 Japanese PHHI patients, all exons of SUR1 and Kir6.2 genes were analysed by polymerase chain reaction (PCR) and direct sequencing. Four patients responded to diazoxide, and nine patients underwent a subtotal pancreatectomy. Histologically, seven patients were diagnosed to have a focal form and two a diffuse form of the disease. Results: We found nine novel mutations in the SUR1 gene and two in the Kir6.2 gene. In the SUR1 gene mutations, three were nonsense mutations (Y512X, Y1354X and G1469X), one was a one-base deletion in exon 7, and two were missense mutations in the nucleotide-binding domain 2 (K1385Q, R1487K). The other three mutations occurred in introns 14, 29 and 36, which might cause aberrant splicing of RNA. Two siblings in one family were heterozygotes for a missense mutation, K1385Q, which was maternally inherited. In Kir6.2 gene screening, one patient was found to be a compound heterozygote of a missense mutation (R34H) and a one-base deletion (C344fs/ter). Conclusion: The novel mutations reported here could be pathological candidates for PHHI in Japan. They also reveal that SUR1 and Kir6.2 mutations in the Japanese population exhibit heterogeneity and that they occurred at a frequency similar to other genetic populations.

Original languageEnglish
Pages (from-to)458-465
Number of pages8
JournalClinical Endocrinology
Volume62
Issue number4
DOIs
Publication statusPublished - Apr 1 2005

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Congenital Hyperinsulinism
Adenosine Triphosphate
Genotype
Mutation
Missense Mutation
Genes
Heterozygote
Exons
Glucose Metabolism Disorders
Sulfonylurea Receptors
RNA Splicing
Diazoxide
KATP Channels
Pancreatectomy
Nonsense Codon
Potassium Channels
Population Genetics
Population Characteristics
Introns
Siblings

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Genotypes of the pancreatic β-cell K-ATP channel and clinical pnenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy. / Ohkubo, Kumiko; Nagashima, Mariko; Naito, Yuko; Taguchi, Tomoaki; Suita, Sachiyo; Okamoto, Nobuhiko; Fujinaga, Hideshi; Tsumura, Kumi; Kikuchi, Kiyoshi; Ono, Junko.

In: Clinical Endocrinology, Vol. 62, No. 4, 01.04.2005, p. 458-465.

Research output: Contribution to journalArticle

Ohkubo, Kumiko ; Nagashima, Mariko ; Naito, Yuko ; Taguchi, Tomoaki ; Suita, Sachiyo ; Okamoto, Nobuhiko ; Fujinaga, Hideshi ; Tsumura, Kumi ; Kikuchi, Kiyoshi ; Ono, Junko. / Genotypes of the pancreatic β-cell K-ATP channel and clinical pnenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy. In: Clinical Endocrinology. 2005 ; Vol. 62, No. 4. pp. 458-465.
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T1 - Genotypes of the pancreatic β-cell K-ATP channel and clinical pnenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy

AU - Ohkubo, Kumiko

AU - Nagashima, Mariko

AU - Naito, Yuko

AU - Taguchi, Tomoaki

AU - Suita, Sachiyo

AU - Okamoto, Nobuhiko

AU - Fujinaga, Hideshi

AU - Tsumura, Kumi

AU - Kikuchi, Kiyoshi

AU - Ono, Junko

PY - 2005/4/1

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N2 - Objective: Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a disorder of glucose metabolism that is characterized by dysregulated secretion of insulin from pancreatic β-cells. This disease has been reported to be associated with mutations of the sulfonylurea receptor SUR1 (ABCC8) or the inward-rectifying potassium channel Kir6.2 (KCNJ11), which are two subunits of the pancreatic β-cell ATP-sensitive potassium channel. Patients and Methods: In 14 Japanese PHHI patients, all exons of SUR1 and Kir6.2 genes were analysed by polymerase chain reaction (PCR) and direct sequencing. Four patients responded to diazoxide, and nine patients underwent a subtotal pancreatectomy. Histologically, seven patients were diagnosed to have a focal form and two a diffuse form of the disease. Results: We found nine novel mutations in the SUR1 gene and two in the Kir6.2 gene. In the SUR1 gene mutations, three were nonsense mutations (Y512X, Y1354X and G1469X), one was a one-base deletion in exon 7, and two were missense mutations in the nucleotide-binding domain 2 (K1385Q, R1487K). The other three mutations occurred in introns 14, 29 and 36, which might cause aberrant splicing of RNA. Two siblings in one family were heterozygotes for a missense mutation, K1385Q, which was maternally inherited. In Kir6.2 gene screening, one patient was found to be a compound heterozygote of a missense mutation (R34H) and a one-base deletion (C344fs/ter). Conclusion: The novel mutations reported here could be pathological candidates for PHHI in Japan. They also reveal that SUR1 and Kir6.2 mutations in the Japanese population exhibit heterogeneity and that they occurred at a frequency similar to other genetic populations.

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