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Mutations in the ABCC8 (SUR1 subunit of the K ATP channel) gene are associated with a variable clinical phenotype
Author(s) -
Klupa Tomasz,
Kowalska Irina,
Wyka Krystyna,
Skupien Jan,
Patch AnnMarie,
Flanagan Sarah E.,
Noczynska Anna,
Arciszewska Malgorzata,
Ellard Sian,
Hattersley Andrew T.,
Sieradzki Jacek,
Mlynarski Wojciech,
Malecki Maciej T.
Publication year - 2009
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.2008.03478.x
Subject(s) - mutation , endocrinology , compound heterozygosity , heterozygote advantage , medicine , proband , hyperinsulinemic hypoglycemia , diabetes mellitus , gene mutation , biology , genetics , gene , genotype , hypoglycemia
Summary 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 HbA 1c of 7·3%, whereas the F132V mutation carrier was on 0·66 IU/kg/day of insulin with HbA 1c 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.