ABCMdb

PMID: 17389331

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., [PubMed]

Sentences

No. Mutations Sentence Comment

34 ABCC8 p.Leu582Val Eleven patients are of French origin, four are Spanish (16), and one (KS-L582V) (Table 1) is from Turkey. Login to comment 35 ABCC8 p.Leu582Val Eleven patients are of French origin, four are Spanish (16), and one (KS-L582V) (Table 1) is from Turkey. Login to comment 38 ABCC8 p.Val324Met ABCC8 p.Glu208Lys ABCC8 p.Ala269Asp ABCC8 p.Val1523Met ABCC8 p.Arg825Trp ABCC8 p.Arg1379His 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 ABCC8 p.Leu582Val ABCC8 p.Val324Met ABCC8 p.Glu208Lys ABCC8 p.Ala269Asp ABCC8 p.Val1523Met ABCC8 p.Arg1182Gln ABCC8 p.Arg825Trp ABCC8 p.Arg1379His 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 40 ABCC8 p.Leu582Val ABCC8 p.Arg1182Gln The two other mutations, L582V (c.1744Cb0e;G) and R1182Q (c.3545Gb0e;A), had been previously described by our group in three independent families with TND cases (13). Login to comment 43 ABCC8 p.Leu213Arg ABCC8 p.Glu208Lys E208K is close to the L213R mutation-previously found in a PND patient (13)-both of which lie in the intracellular L0-linker that controls the channel POmax (17). Login to comment 44 ABCC8 p.Leu213Arg ABCC8 p.Val324Met ABCC8 p.Glu208Lys ABCC8 p.Val1523Met ABCC8 p.Arg1379His V324M is located in the transmembrane domain (TMD)6 of TMD1, and R1379H and V1523M are in the nucleotide-binding domain 2, the domain argued to hydrolyze MgATP. Login to comment 45 ABCC8 p.Val324Met ABCC8 p.Ala269Asp ABCC8 p.Val1523Met ABCC8 p.Arg825Trp ABCC8 p.Arg1379His A269D and R825W lie in the helical intracellular coupling domains (4). Login to comment 46 ABCC8 p.Ala269Asp ABCC8 p.Arg825Trp A269D and R825W lie in the helical intracellular coupling domains (4). Login to comment 47 ABCC8 p.Ala269Asp One case (NJ-A269D) is too young to be diagnosed as a transient or permanent case. Login to comment 48 ABCC8 p.Val324Met ABCC8 p.Ala269Asp ABCC8 p.Arg1379His 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 49 ABCC8 p.Val324Met ABCC8 p.Arg1379His 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 ABCC8 p.Leu582Val ABCC8 p.Glu208Lys ABCC8 p.Ala269Asp ABCC8 p.Arg825Trp 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 ABCC8 p.Leu582Val ABCC8 p.Glu208Lys ABCC8 p.Ala269Asp ABCC8 p.Val1523Met ABCC8 p.Arg1182Gln ABCC8 p.Arg825Trp The R1182Q and V1523M mutations were not identified in either parent, consistent with de novo mutations. Login to comment 52 ABCC8 p.Val324Met ABCC8 p.Val1523Met ABCC8 p.Arg1182Gln ABCC8 p.Arg1379His The V324M and R1379H mutations tested negative in the mothers, and the two fathers were not available for genetic testing. Login to comment 53 ABCC8 p.Val324Met ABCC8 p.Arg1379His The V324M and R1379H mutations tested negative in the mothers, and the two fathers were not available for genetic testing. Login to comment 59 ABCC8 p.Val324Met ABCC8 p.Arg825Trp Three TND patients (NJ-A269D, LM-R825W, and GK-V324M) were small for gestational age (Ͻ3rd percentile). Login to comment 60 ABCC8 p.Val324Met ABCC8 p.Arg825Trp Three TND patients (NJ-A269D, LM-R825W, and GK-V324M) were small for gestational age (b0d;3rd percentile). Login to comment 61 ABCC8 p.Val324Met In patient GK-V324M, recurrence of diabetes occurred at 9 years of age and was treated with insulin injections. Login to comment 62 ABCC8 p.Val324Met ABCC8 p.Val324Met After ABCC8 sequencing had been performed and after the agreement of the French health authorities had been granted for sulfonylureas treatment in children with a SUR1 mutation, the patient GK-V324M was successfully transferred to glibenclamide (Table 1). Login to comment 63 ABCC8 p.Val324Met ABCC8 p.Arg1379His One patient (CD-R1379H) has a hyperactivity disorder with attention deficit disorder associated with speech developmental delay and feeding behavior anomalies. Login to comment 64 ABCC8 p.Arg1379His One patient (CD-R1379H) has a hyperactivity disorder with attention deficit disorder associated with speech developmental delay and feeding behavior anomalies. Login to comment 65 ABCC8 p.Ala269Asp 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 ABCC8 p.Leu582Val ABCC8 p.Glu208Lys ABCC8 p.Ala269Asp ABCC8 p.Ala269Asp ABCC8 p.Arg825Trp 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 ABCC8 p.Leu582Val ABCC8 p.Leu582Val ABCC8 p.Glu208Lys ABCC8 p.Ala269Asp ABCC8 p.Ala269Asp ABCC8 p.Arg825Trp ABCC8 p.Arg825Trp 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 ABCC8 p.Leu582Val ABCC8 p.Leu582Val ABCC8 p.Ala269Asp ABCC8 p.Arg825Trp 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 69 ABCC8 p.Leu582Val ABCC8 p.Glu208Lys In the case of the father of SGM-E208K, glucose intolerance was documented during the oral glucose tolerance test. Login to comment 70 ABCC8 p.Glu208Lys In the case of the father of SGM-E208K, glucose intolerance was documented during the oral glucose tolerance test. In the comparison of the present cohort of ND-SUR1 cases (n afd; 8) with our cohort of those linked to KCNJ11/ Kir6.2 mutations (n afd; 18), there was no significant difference in distribution of low birth weight, age of diagnosis, or glucose levels at presentation, as assessed in our previous study (13). Login to comment 77 ABCC8 p.Leu582Val ABCC8 p.Val324Met ABCC8 p.Glu208Lys ABCC8 p.Ala269Asp ABCC8 p.Val1523Met ABCC8 p.Arg1182Gln ABCC8 p.Arg825Trp ABCC8 p.Arg1379His ABCC8 p.Arg1379His 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 78 ABCC8 p.Phe132Leu ABCC8 p.Val324Met and in one patient previously reported with a SUR1 mutation (F132L) and severe DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome (21). Login to comment 79 ABCC8 p.Val324Met ABCC8 p.Arg1379His ߥOnly the mother was screened for the mutation; the father of GK-V324M died, and no information is available on the biological father of CD-R1379H. Login to comment 82 ABCC8 p.Phe132Leu and in one patient previously reported with a SUR1 mutation (F132L) and severe DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome (21). Login to comment 84 ABCC8 p.Leu582Val ABCC8 p.Ala269Asp ABCC8 p.Arg825Trp 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 85 ABCC8 p.Leu582Val Moreover, one of these mutations, L582V, has been shown to cosegregate with diabetes in one previously published family (13). Login to comment 87 ABCC8 p.Leu582Val ABCC8 p.Ala269Asp ABCC8 p.Arg825Trp 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 88 ABCC8 p.Leu582Val Moreover, one of these mutations, L582V, has been shown to cosegregate with diabetes in one previously published family (13). Login to comment