ABCMdb

ABCC8 p.Ala269Asp

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Publications

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. Login to comment

PMID: 18990670 [PubMed] Aittoniemi J et al: "Review. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator."

No. Sentence Comment

204 (a) (b) P45L N72S F132L NH2 A90V V86G COOHL135P exoplasmic cytoplasmic Walker A Walker A linker Walker B linker Walker B V324M E382K C435R L438F L582V R826W H1023Y N1122D R1183Q A1185E R1314H E1327K R1380 L I1425V V1524 L P207S E208K Q211K D212I/N L225P T229I Y263D A269D R306H D209E L213R TMD0 TMD1 TMD2 NBD1 NBD2 CL3 linker site 1 site 2 NBD1 NBD2 R826W R1380 L E1327K I1425V V1524 L Figure 5. Login to comment
207 (a) (b) P45L N72S F132L NH2 A90V V86G COOH L135P exoplasmic cytoplasmic Walker A Walker A linker Walker B linker Walker B V324M E382K C435R L438F L582V R826W H1023Y N1122D R1183Q A1185E R1314H E1327K R1380 L I1425V V1524 L P207S E208K Q211K D212I/N L225P T229I Y263D A269D R306H D209E L213R TMD0 TMD1 TMD2 NBD1 NBD2 CL3 linker site 1 site 2 NBD1 NBD2 R826W R1380 L E1327K I1425V V1524 L Figure 5. Login to comment

PMID: 17389331 [PubMed] Vaxillaire M et al: "New ABCC8 mutations in relapsing neonatal diabetes and clinical features."

No. Sentence Comment

38 We identified eight heterozygous missense ABCC8 mutations in 8 of the 16 patients with neonatal diabetes, six of which have not yet been reported: E208K (c.622GϾA), A269D (c.806CϾA), V324M (c.970GϾA), R825W (c.2473CϾT), R1379H (c.4136GϾA), and V1523M (c.4567GϾA) (Fig. 1). Login to comment
39 The two other mutations, L582V (c.1744CϾG) and R1182Q (c.3545GϾA), had been previously described by our group in three independent families with TND cases (13). Login to comment
45 A269D and R825W lie in the helical intracellular coupling domains (4). Login to comment
47 One case (NJ-A269D) is too young to be diagnosed as a transient or permanent case. Login to comment
48 We have sequenced both parents of the patients (those carrying an ABCC8 mutation, except in two families of probands CD-R1379H and GK-V324M [only the mother sample was available for genetic testing; see Table 1]). Login to comment
50 In the families with E208K, L582V, and R825W mutations, the fathers carried the mutation in the heterozygous state, whereas the A269D mutation in the NJ family was inherited from the mother (Table 1). Login to comment
51 The R1182Q and V1523M mutations were not identified in either parent, consistent with de novo mutations. Login to comment
65 One patient (NJ-A269D) who is 8.7 months old is described with hypotonia without muscle weakness, suggesting a neurological origin. Login to comment
66 Probands SGM-E208K, KS-L582V, and LM-R825W have a mutation inherited from their fathers and proband NJ-A269D from her mother (Table 1). Login to comment
67 In families with the L582V, R825W, and A269D mutations, glucose tolerance tests were performed in the fathers and mother, who were found to be free from diabetes. Login to comment
68 However, the father of KS-L582V has an A1C just above the upper limit of normal, which may suggest minimal glucose disposal disturbances. Login to comment
77 In the ND-SUR1 patients, an apparently mild phenotype, i.e., without neurological features, is observed in the TND families, except in a few cases presenting with PND (13) TABLE1 ClinicalfeaturesinneonataldiabeticpatientsscreenedpositiveforABCC8mutations Patient SGMGKKSLMCNCDDLNJ MutationE208KV324ML582VR825WR1182QR1379HV1523MA269D SexFemaleMaleMaleFemaleFemaleMaleMaleFemale TypeofdiabetesTNDTNDTNDTNDTNDTNDPND Notyet known Atbirth Weight(g/percentile)1,790/321,660/Ͻ33,250/282,300/Ͻ32,930/103,150/432,710/312,390/Ͻ3 Gestationweek33.53739394138.53739 Atpresentation Age(days)1112361013426766 Weight(g)1,7904,2904,3002,5203,0003,6903,6605,100 PresentationGlucose monitoring KetoacidosisKetoacidosisGlucose monitoring WeightlossKetoacidosisKetoacidosisKetoaciduria Glucose(mmol/l)12.424.160.516.824.164.23627.5 Autoantibodies00000000 Insulindose(units⅐kg-1 ⅐day-1 )0.1012.400.300.720.502.500.72 PancreasultrasonographyNANANNNNNN Currentstatus Age(months)712728134833188.7 Height(cm/SD)63/-1.6134.5/-0.790.2/0.672.5/-0.4101.2/0.296/184/1.370/0.8 Weight(kg/percentile)6.15/323.6/Ͻ313.5/759.62/5614.9/5017.5/Ͼ9711/318.52/50 Diabetes(yes[ϩ],no[-])-ϩ(9)*----ϩϩ Insulindose(units⅐kg-1 ⅐day-1 )00†00000.600.62 A1Catlastexamination(%)4.56.05.15.05.45.05.58.9 Neurologicalfeatures MuscleweaknessNoNoNoNoNoNoNoNo MotordevelopmentaldelayNoNoNoNoNoNoNoNo EpilepsyNoNoNoNoNoNoNoNo MentaldevelopmentaldelayNoNoNoNoNoNoNoNo SpeechdevelopmentaldelayNoYesNoNoNoYesNoNo DysmorphicfeaturesNoNoNoNoNoNoNoNo OtherfeaturesNoNoNoNoNoHyperkinesia, troubleof feeding behavior NoHypotonia ParentwithamutationFatherNone‡FatherFatherNoneNone‡NoneMother Glucosetolerance§IGT-NN---N Ageatexamination(year)41-3129---25 A1Catlastexamination(%)¶5.4-6.1NA---5.2 BMIatlastexamination(kg/m2 )27-2422---NA *Ageatrelapse,inyear.†PatientGK-V324Mwassuccessfullyswitchedtoglibenclamide(gliburide)attheageof9.5years(currentdose2.5mg/day;weight25kg).‡Onlythemotherwas screenedforthemutation;thefatherofGK-V324Mdied,andnoinformationisavailableonthebiologicalfatherofCD-R1379H.§Assessedbyanoralglucosetolerancetest.¶Upperlimit ofnormalvaluesforA1C:5.6%.IGT,impairedglucosetolerance;N,normal;NA,notavailable. Login to comment
84 We believe that those mutations (A269D, L582V, and R825W) are not polymorphisms, as they were shown to be absent from a large number of euglycemic subjects. Login to comment
46 A269D and R825W lie in the helical intracellular coupling domains (4). Login to comment
87 Strikingly, some of the parents of the probands (two fathers and one mother) are carriers of an ABCC8 mutation likely to be responsible for neonatal diabetes in their children and, despite this, have normal glucose tolerance as shown in an oral glucose tolerance test. We believe that those mutations (A269D, L582V, and R825W) are not polymorphisms, as they were shown to be absent from a large number of euglycemic subjects. Login to comment