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 language | English |
|---|---|
| Pages (from-to) | 328-336 |
| Number of pages | 9 |
| Journal | Diabetes |
| Volume | 56 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2007 |
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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 journal › Article
}
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.
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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 -