ABCC8 p.Val86Ala

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PMID: 17213273 [PubMed] Stanik J et al: "Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers."
No. Sentence Comment
8 One patient has a novel V86A mutation in the ABCC8 gene and was also substituted with SU.
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ABCC8 p.Val86Ala 17213273:8:24
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108 SK-1 SK-2 SK-3 SK-4 SK-5 SK-6 SK-7 SK-8 Diagnosis KCNJ11 mutation R201H KCNJ11 mutation L164P, VHC PNDM, unknown etiologya KCNJ11 mutation H46Y Wolcott-Rallison syndrome KCNJ11 mutation R201H Intermediate DEND, not analyzed ABCC8 mutation V86A Gender Female Female Male Female Male Male Female Male Birth weight (g) 3000 2600 2450 3500 3750 2480 1450 2900 Gestation (wk) 39 40 40 40 42 40 37 40 DM onset (wk) 18 5 10 15 11 4 Ͻ1 9 Dysmorphic features No No No Mild No No Yes No Seizures No No No No No No No No Developmental delay No No No No No No Yes No Autoantibodies Negative Negative Negative Negative Negative Negative Negative Negative Therapy after onset Insulin Insulin Insulin Insulin Insulin Insulin Insulin Insulin Insulin (IU/kg⅐d) 0.6 1.24 0.8 1 0.8 0.66 0.5 0.45 C-peptide (ng/ml) 0.01 0.01 0.42 0.04 0.18 0.11 0.12 0.01 Current status Current age (yr) 25 19 13 12 11 11 Deceased at 18 months 5 Current therapy SU Insulin Insulin SU Insulin SU Insulin SU Current HbA1c (%) 7.0 15.2 12.2 6.6 15.1 5.7 Not available 6.9 DM, Diabetes mellitus; VHC, virus hepatitis C. a Negative for mutations in KCNJ11, SUR1, IPF1, and NEUROD1 genes.
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ABCC8 p.Val86Ala 17213273:108:239
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111 V86A (c.257TϾC) is a novel mutation in exon 2 of the ABCC8 gene that results in the substitution of alanine for valine at codon 86 (p.Val86Ala).
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ABCC8 p.Val86Ala 17213273:111:0
status: NEW
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ABCC8 p.Val86Ala 17213273:111:106
status: NEW
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ABCC8 p.Val86Ala 17213273:111:140
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118 Clinical characteristics of the ABCC8 mutation carrier Patient SK-8 with the V86A mutation was born in the 40th gestational week with birth weight of 2800 g and developed diabetes in his second month of life as manifested with polyuria, polydipsia, and failure to thrive during a respiratory tract infection.
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ABCC8 p.Val86Ala 17213273:118:77
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PMID: 17919176 [PubMed] Patch AM et al: "Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period."
No. Sentence Comment
85 Five residues are sites for different amino acid substitutions: V86A/G, F132L/V, D212I/N, R1183Q/W and R1380C/H/L.
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ABCC8 p.Val86Ala 17919176:85:64
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161 Affected probands and family members can be separated into three distinct groups based T229I/T229I ABCC8 mutations Transient Neonatal Diabetes Mellitus Recessive homozygous mutations R826W (2) H1024Y R1183Q (2) R1183W (5) R1314H R1380C (3) R1380H R1380L (2) D209E D212I D212N R306H V324M C435R L451P L582V (2) Dominant heterozygous mutations Permanent Neonatal Diabetes Mellitus E382K/E382K A1185E/A1185E Mosaic N72S Recessive homozygous or mosaic mutations P45L/G1401R E208K/Y263D T229I/V1523L L438F/M1290V P207S/c.536del4 E1327K+V1523A/ c.1327ins10 Recessive compound heterozygous mutations 1K Dominant heterozygous mutations D209E Q21 L213R L225P(2) I1425V V86A V86G F132L (2) F132V L135P Fig. 2 A diagram illustrating the inheritance of ABCC8 mutations in probands with permanent and transient forms of neonatal diabetes.
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ABCC8 p.Val86Ala 17919176:161:660
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163 Permanent Neonatal Diabetes Mellitus Transient Neonatal Diabetes Mellitus 1 5 10 15 20 25 30 35 39 N72S V86A V86G F132L F132V L135PP45L P207S E208K D209E Q211K L213R L225P T229I Y263D D209E D212I D212N T229I R306H V324M L438F L451P E382K R826W R1183W R1183Q A1185E E1327K R1314H M1290V R1380C R1380H R1380L G1401R V1523A V1523L H1024YC435R L582V I1425V Fig. 3 The location of missense mutations causing neonatal diabetes within the coding sequence of ABCC8.
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ABCC8 p.Val86Ala 17919176:163:104
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176 No neurological features were reported in R1183W/Q A1185E E1327K G1401R V1523A/L NBD1 NBD2 outside membrane inside P45L N72S F132L/V L135P P207S E208K D209E Q211K D212I/N L213R L225P T229I Y263D E382K V86A/G L438F C435R R1380C/H/L L451P R826W TMD0 TMD1 TMD2 R306H V324M L582V H1024Y I1425V R1314H M1290V Fig. 4 A schematic of the membrane topologies of SUR1 showing the location of the ABCC8 missense mutations causing neonatal diabetes.
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ABCC8 p.Val86Ala 17919176:176:201
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197 Genotype-phenotype Correlation Most of the dominantly acting mutations located in exons 2-5 of the ABCC8 gene (V86A/G, F132L/V, L135P, D209E, Q211K, L213R and L225P) cause PNDM.
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ABCC8 p.Val86Ala 17919176:197:111
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224 Furthermore, different mutations at the same residue (V86A/G, F132L/V, D212I/N, R1183Q/W and R1380C/H/L) cause either PNDM (V86 and F132) or biphasic TNDM (D212, R1183 and R1380), suggesting a different pathological mechanism.
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ABCC8 p.Val86Ala 17919176:224:54
status: NEW
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PMID: 20922570 [PubMed] Edghill EL et al: "Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11."
No. Sentence Comment
85 One of the most notable R1183W/Q A1185E E1327K G1401R V1523A/L V1524M R1531A NBD1 NBD2 outside membrane inside P45L N72S F132L/V L135P P207S E208K D209E Q211K D212I/N L213R L225P T229I Y263D A269D/N E382K V86A/G R1380C/H/L C435R L438F M1290V L451P R826W R1314H TMD0 TMD1 TMD2 R306H V324M L582V H1024Y I1425V A90V Y356C R521Q N1123D R1153G T1043TfsX74 Fig. 3 Schematic representation of 50 ABCC8 mutations which cause neonatal diabetes.
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ABCC8 p.Val86Ala 20922570:85:205
status: NEW
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PMID: 18025408 [PubMed] Rafiq M et al: "Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations."
No. Sentence Comment
54 Doses Table 1-Clinical characteristics of patients with SUR1 mutations according to success of treatment with sulfonylureas Characteristic All patients Patients with successful sulfonylurea treatment Patients with unsuccessful sulfonylurea treatment P* n 27 23 4 Mutation (number of patients) NA V86G†, P45L/G1401R- (2)†, D209E (3)†, T229I/V1523L†, Q211K†, V86A (2)†, E1507G, V215I/V607M, E208K/Y263D†, R1380L (2)‡, D212I (3)§, T229I/T229I‡, R1183W§, L225P†, R826W, and D209N F132L (2)†, F132V†, and N72S† (mosaic).
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ABCC8 p.Val86Ala 18025408:54:392
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56 Doses Table 1-Clinical characteristics of patients with SUR1 mutations according to success of treatment with sulfonylureas Characteristic All patients Patients with successful sulfonylurea treatment Patients with unsuccessful sulfonylurea treatment P* n 27 23 4 Mutation (number of patients) NA V86Gߤ, P45L/G1401R- (2)ߤ, D209E (3)ߤ, T229I/V1523Lߤ, Q211Kߤ, V86A (2)ߤ, E1507G, V215I/V607M, E208K/Y263Dߤ, R1380L (2)ߥ, D212I (3)&#a7;, T229I/T229Iߥ, R1183W&#a7;, L225Pߤ, R826W, and D209N F132L (2)ߤ, F132Vߤ, and N72Sߤ (mosaic).
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ABCC8 p.Val86Ala 18025408:56:387
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PMID: 22306677 [PubMed] Mak CM et al: "Personalized medicine switching from insulin to sulfonylurea in permanent neonatal diabetes mellitus dictated by a novel activating ABCC8 mutation."
No. Sentence Comment
33 The last patient carried a heterozygous mutation (p.V86A) in ABCC8 with baseline C-peptide of 0.003nmol/L and initially required insulin of 0.45 IU/kg/d.
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ABCC8 p.Val86Ala 22306677:33:52
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PMID: 19021632 [PubMed] Klupa T et al: "Mutations in the ABCC8 (SUR1 subunit of the K(ATP) channel) gene are associated with a variable clinical phenotype."
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).
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ABCC8 p.Val86Ala 19021632:7:219
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10 The C-peptide level varied from 0Æ1 ng/ml (F132V) to 0Æ75 ng/ml (V86A).
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ABCC8 p.Val86Ala 19021632:10:75
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14 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.
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ABCC8 p.Val86Ala 19021632:14:70
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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.
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ABCC8 p.Val86Ala 19021632:34:110
status: NEW
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ABCC8 p.Val86Ala 19021632:34:130
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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.
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ABCC8 p.Val86Ala 19021632:35:144
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38 Two probands had relapsed transient diabetes (V86A and R826W heterozygotes).
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ABCC8 p.Val86Ala 19021632:38:46
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39 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.
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ABCC8 p.Val86Ala 19021632:39:21
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46 Microsatellite analysis confirmed that the F132V and V86A mutations had arisen de novo.
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ABCC8 p.Val86Ala 19021632:46:53
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51 The C-peptide level varied from 0Æ1 ng/ml (F132V) to 0Æ75 ng/ml (V86A).
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ABCC8 p.Val86Ala 19021632:51:75
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55 This was fully successful in probands with R826W and V86A mutations (Families B and C, respectively).
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ABCC8 p.Val86Ala 19021632:55:53
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60 All examined auto-antibodies were present in high concentration in one diabetic mutation carrier, a 16-year-old girl with the V86A substitution.
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ABCC8 p.Val86Ala 19021632:60:126
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65 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.
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ABCC8 p.Val86Ala 19021632:65:18
status: NEW
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66 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.
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ABCC8 p.Val86Ala 19021632:66:59
status: NEW
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ABCC8 p.Val86Ala 19021632:66:293
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82 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.
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ABCC8 p.Val86Ala 19021632:82:168
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93 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.
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ABCC8 p.Val86Ala 19021632:93:242
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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).
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ABCC8 p.Val86Ala 19021632:98:455
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PMID: 17668386 [PubMed] Ellard S et al: "Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects."
No. Sentence Comment
27 Apparent spontaneous mutations were confirmed by testing parental and proband DNA samples with use of a panel of six microsatellite markers on chromosome 11p15.11 Heterozygous de novo mutations V86A, V86G, F132L, F132V, D209E, Q211K, and L225P were present in eight patients (table 2).
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ABCC8 p.Val86Ala 17668386:27:194
status: NEW
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