ABCMdb

PMID: 19021632

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., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC8 p.Val86Ala ABCC8 p.Asn23His 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 ABCC8 p.Phe132Val ABCC8 p.Asn23His 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 10 ABCC8 p.Val86Ala ABCC8 p.Phe132Val The C-peptide level varied from 0Æ1 ng/ml (F132V) to 0Æ75 ng/ml (V86A). Login to comment 11 ABCC8 p.Phe132Val We also observed a variable insulin resistance, from moderate (M ¼ 5Æ5 and 5Æ6 mg/kg/ min, respectively, in the two R826W mutation carriers) to severe (M ¼ 2Æ6 mg/kg/min in the F132V mutation carrier). Login to comment 13 ABCC8 p.Phe132Val Interestingly, there was no response to SU in the most insulin resistant F132V mutation carrier despite high dose of glibenclamide. Login to comment 14 ABCC8 p.Val86Ala 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. Login to comment 34 ABCC8 p.Val86Ala ABCC8 p.Val86Ala ABCC8 p.Phe132Val ABCC8 p.Phe132Val ABCC8 p.Asn23His ABCC8 p.Asn23His 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 ABCC8 p.Val86Ala ABCC8 p.Phe132Val ABCC8 p.Asn23His 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 ABCC8 p.Asn23His Asparagine at residue 23 is conserved from human to Xenopus and N23H was not detected in 210 normal chromosomes. Login to comment 38 ABCC8 p.Val86Ala Two probands had relapsed transient diabetes (V86A and R826W heterozygotes). Login to comment 39 ABCC8 p.Val86Ala The patient with the V86A mutation was treated with insulin from diagnosis until the age of 6 years when she stopped treatment for 2 years. Login to comment 43 ABCC8 p.Asn23His 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 44 ABCC8 p.Phe132Val Both he and the F132V mutation carrier who has been treated with insulin since the age of 5 months were classified as having PNDM. Login to comment 46 ABCC8 p.Val86Ala ABCC8 p.Phe132Val Microsatellite analysis confirmed that the F132V and V86A mutations had arisen de novo. Login to comment 48 ABCC8 p.Asn23His The N23H and R826W mutations were inherited by the proband of family D from two different sides of the family. Login to comment 49 ABCC8 p.Asn23His There is no evidence of diabetes in his father, mother or maternal grandmother, who is carrier of N23H or R826W. Login to comment 50 ABCC8 p.Phe132Val There were striking differences in the clinical picture of SUR1 related diabetes as, for example, the compound heterozygote was controlled on diet alone with HbA1c of 7Æ3%, while the F132V mutation carrier wason47unitsof insulin/daywith HbA1c of 11Æ7%. Login to comment 51 ABCC8 p.Val86Ala ABCC8 p.Phe132Val The C-peptide level varied from 0Æ1 ng/ml (F132V) to 0Æ75 ng/ml (V86A). Login to comment 53 ABCC8 p.Phe132Val Interestingly, there was some evidence of a variable degree of resistance to insulin: from moderate (M ¼ 5Æ5 and 5Æ6 mg/kg/min, respectively, in two R826W mutation carriers) to severe (M ¼ 2Æ6 mg/kg/min in the F132V mutation carrier). Login to comment 55 ABCC8 p.Val86Ala This was fully successful in probands with R826W and V86A mutations (Families B and C, respectively). Login to comment 59 ABCC8 p.Phe132Val There was no clinical response to SU treatment in the most insulin resistant F132V carrier of the mutation despite 6 months of high dose SUs (> 1 mg/kg/day of glibenclamide, with a maximum dose of 1Æ5 mg/kg/day). Login to comment 60 ABCC8 p.Val86Ala All examined auto-antibodies were present in high concentration in one diabetic mutation carrier, a 16-year-old girl with the V86A substitution. Login to comment 61 ABCC8 p.Asn23His In addition, a compound heterozygote with N23H and R826W mutations had a slightly elevated IA2-Ab level. Login to comment 65 ABCC8 p.Val86Ala The girl with the V86A mutation carried DRB1*1501-DQA1*0102- DQB1*0602 and DRB1*11-DQA1*0501-DQB1*0301 haplotypes, one of them associated with strong and one with moderate protection from T1DM.21 Discussion We report here the results of a search for subjects with neonatal diabetes due to mutations in the ABCC8 gene in a cohort of patients from Poland. Login to comment 66 ABCC8 p.Val86Ala ABCC8 p.Val86Ala ABCC8 p.Phe132Leu ABCC8 p.Val86Gly ABCC8 p.Phe132Val The causative relationships between both de novo variants, V86A and F132V, and diabetic phenotype are evident, particularly as different mutations at these residues (F132L and V86G) were previously described in other cases of neonatal diabetes4,18 in addition to another case of PNDM with the V86A mutation.20 The R826W mutation was found in two families in this study but they are not known to share a common ancestor. Login to comment 76 ABCC8 p.Asn23His 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 ABCC8 p.Asn23His The shortcoming of our report is the absence of functional studies for this N23H variant. Login to comment 79 ABCC8 p.Phe132Val No neurological symptoms were present in all identified ABCC8 gene mutation carriers, including the patient with the F132V substitution. Login to comment 80 ABCC8 p.Phe132Leu Interestingly, both previously reported carriers of the mutation at this residue, F132L, showed some degree of developmental delay.18 A genotype/phenotype correlation, that includes the clinical picture and the response to the SU, has been reported for both KCNJ11 and ABCC8 mutations,22,23 although the correlation for Kir6Æ2 is strongest. Login to comment 82 ABCC8 p.Val86Ala One notable exception is a patient with the most common PNDM Kir6Æ2 mutation R201H who experienced a 5-years remission period.24 In our study the patient with the V86A mutation had a period of remission between the age of 6 and 8 years and was therefore classified as relapsed TNDM. Login to comment 86 ABCC8 p.Phe132Val Forexample, a woman with the most severe diabetes, the carrier of the F132V mutation who failed to respond to SU, also had the largest degree of resistance to insulin. Login to comment 93 ABCC8 p.Val86Ala The frequency of positive ICAs and ICA in the general population of children and adolescence may reach 4Æ1% and 2Æ0% as earlier reported, respectively.26 The presence of all three positive autoantibodies, like in the carrier of the V86A mutation, was very rare (< 1/ 1000) and it was associated with progression to T1DM in individuals with predisposing HLA haplotypes. Login to comment 98 ABCC8 p.Val86Ala ABCC8 p.Phe132Val ABCC8 p.Asn23His 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). 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