ABCMdb

ABCC8 p.Asn23His

Predicted by SNAP2:	A: D (63%), C: D (75%), D: D (71%), E: D (71%), F: D (71%), G: D (59%), H: N (61%), I: D (71%), K: D (71%), L: D (71%), M: D (80%), P: D (75%), Q: N (57%), R: D (71%), S: N (57%), T: N (72%), V: D (71%), W: D (85%), Y: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: D, P: D, Q: N, R: N, S: N, T: N, V: D, W: D, Y: D,

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[hide] Mutations in the ABCC8 (SUR1 subunit of the K(ATP)... Clin Endocrinol (Oxf). 2009 Sep;71(3):358-62. Epub 2008 Nov 18. Klupa T, Kowalska I, Wyka K, Skupien J, Patch AM, Flanagan SE, Noczynska A, Arciszewska M, Ellard S, Hattersley AT, Sieradzki J, Mlynarski W, Malecki MT
Mutations in the ABCC8 (SUR1 subunit of the K(ATP) channel) gene are associated with a variable clinical phenotype.
Clin Endocrinol (Oxf). 2009 Sep;71(3):358-62. Epub 2008 Nov 18., [PMID:19021632]

Abstract [show]
OBJECTIVE: Mutations in the ABCC8 gene encoding the SUR1 subunits of the beta-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.

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No. Sentence Comment
7 Results We identified two probands with permanent ND (one heterozygousF132Vmutationcarrierandonecompoundheterozygote with N23H and R826W mutations) and two others with relapsed transient ND (heterozygotes for R826W and V86A substitutions, respectively). Login to comment
9 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 7Æ3%, whereas the F132V mutation carrier was on 0Æ66 IU/ kg/day of insulin with HbA1c of 11Æ7%. Login to comment
34 Three were heterozygous carriers of the F132V (c.394T > G; p.Phe132Val), R826W (c.2476T > C; p.Arg826Trp) and V86A (c.257T > C; p.Val86Ala) substitutions; one patient was a compound heterozygote who carried two, N23H (c.67 A > C; p.Asn23His) and R826W, mutations in trans. Login to comment
35 The patient with the F132V mutation was included in a previous publication,18 R826W has previously been reported in two probands with TNDM,2,19 V86A was identified in a Slovakian patient with PNDM,20 but N23H is novel. Login to comment
37 Asparagine at residue 23 is conserved from human to Xenopus and N23H was not detected in 210 normal chromosomes. Login to comment
43 The 8-year-old child compound heterozygous for R826W and N23H was treated with insulin for 4 years following diagnosis, but since stopping treatment his HbA1c has never been below 6% and is currently 7Æ3%. Login to comment
48 The N23H and R826W mutations were inherited by the proband of family D from two different sides of the family. Login to comment
49 There is no evidence of diabetes in his father, mother or maternal grandmother, who is carrier of N23H or R826W. Login to comment
61 In addition, a compound heterozygote with N23H and R826W mutations had a slightly elevated IA2-Ab level. Login to comment
76 Interestingly, in family D, the only diabetic patient among the three R826W mutation carriers was the compound heterozygote who also had the N23H substitution. Login to comment
77 The shortcoming of our report is the absence of functional studies for this N23H variant. Login to comment
98 Clinical characteristics of diabetic ABCC8 mutation carriers Patient`s number and ABCC8 mutation Treatment at the study entry Neurological symptoms Diabetic complications Current treatment BMI (kg/m2 ) C-peptide (ng/ml) HbA1c (%) M [mg/ (kg· min)] Positive autoantibodies Pol6-1 F132V Insulin- 0Æ66 IU/kg/day Not present Diabetic retinopathy Insulin 1Æ19 IU/kg/day 21Æ7 22Æ4 0Æ1 11Æ7 12Æ0 2Æ6 N/A None Pol10-1 V86A Insulin- 0Æ77 IU/kg/day Not present None Glipizide GITS 20 mg/day 21Æ5 21Æ5 0Æ7 2Æ2 12Æ2 5Æ8 N/A N/A ICA, GADA, IA2-Ab Pol20-1 Insulin 0Æ37 IU/kg/day Not present None Glipizide GITS 22Æ53 0Æ66 6Æ5 5Æ6 None R826W 10 mg/day 23Æ45 2Æ07 5Æ4 8Æ73 Pol20-3 Insulin 0Æ40 IU/kg/day Not present None Glibenclamide 45 mg/day 21Æ0 0Æ39 8Æ5 5Æ5 None R826W Insulin 0Æ20 IU/kg/day 19Æ7 0Æ37 7Æ7 6Æ5 Pol29-1 Diet Not present None Diet 13Æ8 0Æ16 7Æ3 N/A IA2-Ab R826W/N23H 16Æ1 7Æ2 N/A For BMI, C-peptide, HbA1c and M parameter we provided the initial data and the results obtained during the re-examination performed at the 3 month for all patients, but Pol6-1 (6 months). Login to comment