Mutations in the ABCC8 (SUR1 subunit of the K-ATP channel) gene are associated with a variable clinical phenotype

Klupa, T., Kowalska, I., Wyka, K., Skupien, J., Patch, A.-M., Flanagan, S. E., Noczynska, A., Arciszewska, M., Ellard, S., Hattersley, A. T., Sieradzki, J., Mlynarski, W. and Malecki, M. T. (2009) Mutations in the ABCC8 (SUR1 subunit of the K-ATP channel) gene are associated with a variable clinical phenotype. Clinical Endocrinology, 71 3: 358-362. doi:10.1111/j.1365-2265.2008.03478.x

Author Klupa, T.
Kowalska, I.
Wyka, K.
Skupien, J.
Patch, A.-M.
Flanagan, S. E.
Noczynska, A.
Arciszewska, M.
Ellard, S.
Hattersley, A. T.
Sieradzki, J.
Mlynarski, W.
Malecki, M. T.
Title Mutations in the ABCC8 (SUR1 subunit of the K-ATP channel) gene are associated with a variable clinical phenotype
Journal name Clinical Endocrinology   Check publisher's open access policy
ISSN 0300-0664
Publication date 2009-09
Sub-type Article (original research)
DOI 10.1111/j.1365-2265.2008.03478.x
Volume 71
Issue 3
Start page 358
End page 362
Total pages 5
Place of publication Oxford, England, U.K.
Publisher Wiley-Blackwell Publishing
Language eng
Formatted abstract
Objective: Mutations in the ABCC8 gene encoding the SUR1 subunits of the β-cell K-ATP channel cause neonatal diabetes (ND) mellitus. We aimed to determine the contribution of ABCC8 gene to ND in Poland, to describe the clinical phenotype associated with its mutations and to examine potential modifying factors. Patients: The Nationwide Registry of ND in Poland includes patients diagnosed before 6 months of age. In total 16 Kir6.2 negative patients with ND, 14 permanent and 2 relapsed transient, were examined. Measurements: ABCC8 gene mutations were detected by direct sequencing. Mutation carriers' characteristics included clinical data and biochemical parameters. In addition, we performed the hyperinsulinaemic euglycaemic clamp and tested for islet-specific antibodies in diabetic subjects. Results: We identified two probands with permanent ND (one heterozygous F132V mutation carrier and one compound heterozygote with N23H and R826W mutations) and two others with relapsed transient ND (heterozygotes for R826W and V86A substitutions, respectively). One subject, a heterozygous relative with the R826W mutation, had adult onset diabetes. There were striking differences in the clinical picture of the mutation carriers as the carrier of two mutations, N23H and R826W, was controlled on diet alone with HbA1c of 7.3%, whereas the F132V mutation carrier was on 0.66 IU/kg/day of insulin with HbA1c of 11.7%. The C-peptide level varied from 0.1 ng/ml (F132V) to 0.75 ng/ml (V86A). We also observed a variable insulin resistance, from moderate (M = 5.5 and 5.6 mg/kg/min, respectively, in the two R826W mutation carriers) to severe (M = 2.6 mg/kg/min in the F132V mutation carrier). We were able to transfer two patients off insulin to sulphonylurea (SU) and to reduce insulin dose in one other patient. Interestingly, there was no response to SU in the most insulin resistant F132V mutation carrier despite high dose of glibenclamide. All examined auto-antibodies were present in one of the subjects, the V86A mutation carrier, although this did not seem to influence the clinical picture, as we were able to transfer this girl off insulin. Conclusion: Mutations in SUR1 are the cause of about 15% of Kir6.2 negative permanent ND in Poland. The clinical phenotype of SUR1 diabetic mutation carriers is heterogeneous and it appears to be modified by variable sensitivity to insulin. © 2009 The Authors.
Keyword Neonatal Diabetes-Mellitus
Insulin Sensitivity
Activating Mutations
Sulfonylurea Therapy
Oral Sulfonylureas
Kcnj11 Gene
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
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