ABCC8 p.Arg825Trp
| Predicted by SNAP2: | A: D (75%), C: D (71%), D: D (91%), E: D (85%), F: D (85%), G: D (85%), H: D (75%), I: D (80%), K: N (93%), L: D (80%), M: D (66%), N: D (71%), P: D (91%), Q: D (71%), S: D (80%), T: D (80%), V: D (80%), W: D (75%), Y: D (80%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: N, S: D, T: D, V: D, W: D, Y: D, |
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[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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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).
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ABCC8 p.Arg825Trp 17389331:38:219
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.Arg825Trp 17389331:39:219
status: NEW45 A269D and R825W lie in the helical intracellular coupling domains (4).
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ABCC8 p.Arg825Trp 17389331:45:10
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.Arg825Trp 17389331:50:39
status: NEW51 The R1182Q and V1523M mutations were not identified in either parent, consistent with de novo mutations.
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ABCC8 p.Arg825Trp 17389331:51:39
status: NEW59 Three TND patients (NJ-A269D, LM-R825W, and GK-V324M) were small for gestational age (Ͻ3rd percentile).
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ABCC8 p.Arg825Trp 17389331:59:33
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.Arg825Trp 17389331:66:37
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.Arg825Trp 17389331:67:28
status: NEWX
ABCC8 p.Arg825Trp 17389331:67:37
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.Arg825Trp 17389331:68:28
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.Arg825Trp 17389331:77:327
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.Arg825Trp 17389331:84:51
status: NEW46 A269D and R825W lie in the helical intracellular coupling domains (4).
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ABCC8 p.Arg825Trp 17389331:46:10
status: NEW60 Three TND patients (NJ-A269D, LM-R825W, and GK-V324M) were small for gestational age (b0d;3rd percentile).
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ABCC8 p.Arg825Trp 17389331:60:33
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.Arg825Trp 17389331:87:320
status: NEW