ABCC8 p.Ala269Asp
| Predicted by SNAP2: | C: N (93%), D: N (82%), E: N (87%), F: N (82%), G: N (82%), H: N (93%), I: N (93%), K: N (93%), L: N (93%), M: N (93%), N: N (93%), P: N (66%), Q: N (93%), R: N (93%), S: N (93%), T: N (93%), V: N (97%), W: D (63%), Y: N (87%), |
| Predicted by PROVEAN: | C: N, D: D, E: N, F: D, G: N, H: D, I: N, K: N, L: N, M: N, N: N, P: D, Q: N, R: N, S: N, T: N, V: N, W: D, Y: D, |
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[hide] Permanent neonatal diabetes due to activating muta... Rev Endocr Metab Disord. 2010 Sep;11(3):193-8. Edghill EL, Flanagan SE, Ellard S
Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11.
Rev Endocr Metab Disord. 2010 Sep;11(3):193-8., [PMID:20922570]
Abstract [show]
The ATP-sensitive potassium (K(ATP)) channel is composed of two subunits SUR1 and Kir6.2. The channel is key for glucose stimulated insulin release from the pancreatic beta cell. Activating mutations have been identified in the genes encoding these subunits, ABCC8 and KCNJ11, and account for approximately 40% of permanent neonatal diabetes cases. The majority of patients with a K(ATP) mutation present with isolated diabetes however some have presented with the Developmental delay, Epilepsy and Neonatal Diabetes syndrome. This review focuses on mutations in the K(ATP) channel which result in permanent neonatal diabetes, we review the clinical and functional effects as well as the implications for treatment.
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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.Ala269Asp 20922570:85:191
status: NEW[hide] Review. SUR1: a unique ATP-binding cassette protei... Philos Trans R Soc Lond B Biol Sci. 2009 Jan 27;364(1514):257-67. Aittoniemi J, Fotinou C, Craig TJ, de Wet H, Proks P, Ashcroft FM
Review. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator.
Philos Trans R Soc Lond B Biol Sci. 2009 Jan 27;364(1514):257-67., [PMID:18990670]
Abstract [show]
SUR1 is an ATP-binding cassette (ABC) transporter with a novel function. In contrast to other ABC proteins, it serves as the regulatory subunit of an ion channel. The ATP-sensitive (KATP) channel is an octameric complex of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits, and it links cell metabolism to electrical activity in many cell types. ATPase activity at the nucleotide-binding domains of SUR results in an increase in KATP channel open probability. Conversely, ATP binding to Kir6.2 closes the channel. Metabolic regulation is achieved by the balance between these two opposing effects. Precisely how SUR1 talks to Kir6.2 remains unclear, but recent studies have identified some residues and domains that are involved in both physical and functional interactions between the two proteins. The importance of these interactions is exemplified by the fact that impaired regulation of Kir6.2 by SUR1 results in human disease, with loss-of-function SUR1 mutations causing congenital hyperinsulinism and gain-of-function SUR1 mutations leading to neonatal diabetes. This paper reviews recent data on the regulation of Kir6.2 by SUR1 and considers the molecular mechanisms by which SUR1 mutations produce disease.
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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.
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ABCC8 p.Ala269Asp 18990670:204:266
status: NEW207 (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.
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ABCC8 p.Ala269Asp 18990670:207:267
status: NEW[hide] New ABCC8 mutations in relapsing neonatal diabetes... Diabetes. 2007 Jun;56(6):1737-41. Epub 2007 Mar 27. Vaxillaire M, Dechaume A, Busiah K, Cave H, Pereira S, Scharfmann R, de Nanclares GP, Castano L, Froguel P, Polak M
New ABCC8 mutations in relapsing neonatal diabetes and clinical features.
Diabetes. 2007 Jun;56(6):1737-41. Epub 2007 Mar 27., [PMID:17389331]
Abstract [show]
Activating mutations in the ABCC8 gene that encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the pancreatic islet ATP-sensitive K(+) channel (K(ATP) channel) cause both permanent and transient neonatal diabetes. Recently, we have described the novel mechanism where basal Mg-nucleotide-dependent stimulatory action of SUR1 on the Kir6.2 pore is increased. In our present study, we identified six new heterozygous ABCC8 mutations, mainly in patients presenting the transient form of neonatal diabetes (six of eight), with a median duration of initial insulin therapy of 17 months (range 0.5-38.0). Most of these mutations map to key functional domains of SUR1. Whereas Kir6.2 mutations are a common cause of permanent neonatal diabetes and in a few cases associate with the DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome, SUR1 mutations are more frequent in transient (52%) compared with permanent (14%) neonatal diabetes cases screened for ABCC8 in our series. Although ketoacidosis is frequent at presentation, SUR1 mutations associate mainly with transient hyperglycemia, with possible recurrence later in life. One-half of the SUR1 neonatal diabetic patients presented with de novo mutations. In some familial cases, diabetes is not always present in the adult carriers of SUR1 mutations, supporting variability in their clinical expressivity that remains to be fully explained.
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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).
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ABCC8 p.Ala269Asp 17389331:38:171
status: NEW39 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).
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ABCC8 p.Ala269Asp 17389331:39:171
status: NEW45 A269D and R825W lie in the helical intracellular coupling domains (4).
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ABCC8 p.Ala269Asp 17389331:45:0
status: NEW47 One case (NJ-A269D) is too young to be diagnosed as a transient or permanent case.
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ABCC8 p.Ala269Asp 17389331:47:13
status: NEW48 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]).
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ABCC8 p.Ala269Asp 17389331:48:13
status: NEW50 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).
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ABCC8 p.Ala269Asp 17389331:50:128
status: NEW51 The R1182Q and V1523M mutations were not identified in either parent, consistent with de novo mutations.
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ABCC8 p.Ala269Asp 17389331:51:128
status: NEW65 One patient (NJ-A269D) who is 8.7 months old is described with hypotonia without muscle weakness, suggesting a neurological origin.
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ABCC8 p.Ala269Asp 17389331:65:16
status: NEW66 Probands SGM-E208K, KS-L582V, and LM-R825W have a mutation inherited from their fathers and proband NJ-A269D from her mother (Table 1).
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ABCC8 p.Ala269Asp 17389331:66:16
status: NEWX
ABCC8 p.Ala269Asp 17389331:66:103
status: NEW67 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.
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ABCC8 p.Ala269Asp 17389331:67:39
status: NEWX
ABCC8 p.Ala269Asp 17389331:67:103
status: NEW68 However, the father of KS-L582V has an A1C just above the upper limit of normal, which may suggest minimal glucose disposal disturbances.
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ABCC8 p.Ala269Asp 17389331:68:39
status: NEW77 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.
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ABCC8 p.Ala269Asp 17389331:77:354
status: NEW84 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.
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ABCC8 p.Ala269Asp 17389331:84:33
status: NEW46 A269D and R825W lie in the helical intracellular coupling domains (4).
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ABCC8 p.Ala269Asp 17389331:46:0
status: NEW87 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.
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ABCC8 p.Ala269Asp 17389331:87:302
status: NEW