An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes

Ricard Masia, Joseph C. Koster, Stefano Tumini, Francesco Chiarelli, Carlo Colombo, Colin G. Nichols, Fabrizio Barbetti

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Mutations in the pancreatic ATP-sensitive K+ channel (K ATP channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the KATP channel mutations examined result in decreased ATP inhibition, which in turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, which includes developmental delay and epilepsy, in addition to neonatal diabetes (developmental delay, epilepsy, and neonatal diabetes [DEND]), due to a G334D mutation in the Kir6.2 subunit of KATP channel. The patient was wholly unresponsive to sulfonylurea therapy (up to 1.14 mg·kg -1·day-1) and remained insulin dependent. Consistent with the putative role of G334 as an ATP-binding residue, reconstituted homomeric and mixed WT+G334D channels exhibit absent or reduced ATP sensitivity but normal gating behavior in the absence of ATP. In disagreement with the sulfonylurea insensitivity of the affected patient, the G334D mutation has no effect on the sulfonylurea inhibition of reconstituted channels in excised patches. However, in macroscopic rubidium-efflux assays in intact cells, reconstituted mutant channels do exhibit a decreased, but still present, sulfonylurea response. The results demonstrate that ATP-binding site mutations can indeed cause DEND and suggest the possibility that sulfonylurea insensitivity of such patients may be a secondary reflection of the presence of DEND rather than a simple reflection of the underlying molecular basis.

Original languageEnglish
Pages (from-to)328-336
Number of pages9
JournalDiabetes
Volume56
Issue number2
DOIs
Publication statusPublished - Feb 2007

Fingerprint

Adenosine Triphosphate
Mutation
Epilepsy
KATP Channels
Insulin
Rubidium
Developmental Delay, Epilepsy, and Neonatal Diabetes
Binding Sites
Permanent Neonatal Diabetes Mellitus
Inhibition (Psychology)

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes. / Masia, Ricard; Koster, Joseph C.; Tumini, Stefano; Chiarelli, Francesco; Colombo, Carlo; Nichols, Colin G.; Barbetti, Fabrizio.

In: Diabetes, Vol. 56, No. 2, 02.2007, p. 328-336.

Research output: Contribution to journalArticle

Masia, Ricard ; Koster, Joseph C. ; Tumini, Stefano ; Chiarelli, Francesco ; Colombo, Carlo ; Nichols, Colin G. ; Barbetti, Fabrizio. / An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes. In: Diabetes. 2007 ; Vol. 56, No. 2. pp. 328-336.
@article{91dbb3b8bdac41fe803f56a06c2750c7,
title = "An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes",
abstract = "Mutations in the pancreatic ATP-sensitive K+ channel (K ATP channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the KATP channel mutations examined result in decreased ATP inhibition, which in turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, which includes developmental delay and epilepsy, in addition to neonatal diabetes (developmental delay, epilepsy, and neonatal diabetes [DEND]), due to a G334D mutation in the Kir6.2 subunit of KATP channel. The patient was wholly unresponsive to sulfonylurea therapy (up to 1.14 mg·kg -1·day-1) and remained insulin dependent. Consistent with the putative role of G334 as an ATP-binding residue, reconstituted homomeric and mixed WT+G334D channels exhibit absent or reduced ATP sensitivity but normal gating behavior in the absence of ATP. In disagreement with the sulfonylurea insensitivity of the affected patient, the G334D mutation has no effect on the sulfonylurea inhibition of reconstituted channels in excised patches. However, in macroscopic rubidium-efflux assays in intact cells, reconstituted mutant channels do exhibit a decreased, but still present, sulfonylurea response. The results demonstrate that ATP-binding site mutations can indeed cause DEND and suggest the possibility that sulfonylurea insensitivity of such patients may be a secondary reflection of the presence of DEND rather than a simple reflection of the underlying molecular basis.",
author = "Ricard Masia and Koster, {Joseph C.} and Stefano Tumini and Francesco Chiarelli and Carlo Colombo and Nichols, {Colin G.} and Fabrizio Barbetti",
year = "2007",
month = "2",
doi = "10.2337/db06-1275",
language = "English",
volume = "56",
pages = "328--336",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "2",

}

TY - JOUR

T1 - An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes

AU - Masia, Ricard

AU - Koster, Joseph C.

AU - Tumini, Stefano

AU - Chiarelli, Francesco

AU - Colombo, Carlo

AU - Nichols, Colin G.

AU - Barbetti, Fabrizio

PY - 2007/2

Y1 - 2007/2

N2 - Mutations in the pancreatic ATP-sensitive K+ channel (K ATP channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the KATP channel mutations examined result in decreased ATP inhibition, which in turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, which includes developmental delay and epilepsy, in addition to neonatal diabetes (developmental delay, epilepsy, and neonatal diabetes [DEND]), due to a G334D mutation in the Kir6.2 subunit of KATP channel. The patient was wholly unresponsive to sulfonylurea therapy (up to 1.14 mg·kg -1·day-1) and remained insulin dependent. Consistent with the putative role of G334 as an ATP-binding residue, reconstituted homomeric and mixed WT+G334D channels exhibit absent or reduced ATP sensitivity but normal gating behavior in the absence of ATP. In disagreement with the sulfonylurea insensitivity of the affected patient, the G334D mutation has no effect on the sulfonylurea inhibition of reconstituted channels in excised patches. However, in macroscopic rubidium-efflux assays in intact cells, reconstituted mutant channels do exhibit a decreased, but still present, sulfonylurea response. The results demonstrate that ATP-binding site mutations can indeed cause DEND and suggest the possibility that sulfonylurea insensitivity of such patients may be a secondary reflection of the presence of DEND rather than a simple reflection of the underlying molecular basis.

AB - Mutations in the pancreatic ATP-sensitive K+ channel (K ATP channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the KATP channel mutations examined result in decreased ATP inhibition, which in turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, which includes developmental delay and epilepsy, in addition to neonatal diabetes (developmental delay, epilepsy, and neonatal diabetes [DEND]), due to a G334D mutation in the Kir6.2 subunit of KATP channel. The patient was wholly unresponsive to sulfonylurea therapy (up to 1.14 mg·kg -1·day-1) and remained insulin dependent. Consistent with the putative role of G334 as an ATP-binding residue, reconstituted homomeric and mixed WT+G334D channels exhibit absent or reduced ATP sensitivity but normal gating behavior in the absence of ATP. In disagreement with the sulfonylurea insensitivity of the affected patient, the G334D mutation has no effect on the sulfonylurea inhibition of reconstituted channels in excised patches. However, in macroscopic rubidium-efflux assays in intact cells, reconstituted mutant channels do exhibit a decreased, but still present, sulfonylurea response. The results demonstrate that ATP-binding site mutations can indeed cause DEND and suggest the possibility that sulfonylurea insensitivity of such patients may be a secondary reflection of the presence of DEND rather than a simple reflection of the underlying molecular basis.

UR - http://www.scopus.com/inward/record.url?scp=33847025257&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847025257&partnerID=8YFLogxK

U2 - 10.2337/db06-1275

DO - 10.2337/db06-1275

M3 - Article

VL - 56

SP - 328

EP - 336

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 2

ER -