ABCMdb

PMID: 17668386

Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A, Edghill EL, Mackay DJ, Proks P, Shimomura K, Haberland H, Carson DJ, Shield JP, Hattersley AT, Ashcroft FM
Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects.
Am J Hum Genet. 2007 Aug;81(2):375-82. Epub 2007 Jun 29., [PubMed]

Sentences

No. Mutations Sentence Comment

27 ABCC8 p.Val86Ala ABCC8 p.Phe132Leu ABCC8 p.Asp209Glu ABCC8 p.Val86Gly ABCC8 p.Phe132Val ABCC8 p.Gln211Lys ABCC8 p.Leu225Pro 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). Login to comment 29 ABCC8 p.Glu382Lys Two homozygous mutations, E382K and A1185E, were present in probands from pedigrees in which the parents are first Figure 1. Login to comment 35 ABCC8 p.Asn72Ser One patient with PNDM (ISPAD 116) had the N72S mutation and mosaic segmental paternal isodisomy for chromosome 11pter to 11p14, demonstrated by microsatellite analysis of markers D11S2071, D11S922, D11S4177, TH, D11S1318, HBB, D11S4149, D11S1794, D11S904, D11S907, D11S911, D11S4143, and D11S1332. Login to comment 39 ABCC8 p.Thr229Ile ABCC8 p.Tyr263Asp ABCC8 p.Val1523Leu ABCC8 p.Glu208Lys ABCC8 p.Pro45Leu Three probands were compound heterozygotes for the missense mutations P45L/G1401R (ISPAD 47), E208K/Y263D (ISPAD 119), and T229I/V1523L (ISPAD 120). Login to comment 45 ABCC8 p.Pro207Ser The second mutation in this family is a novel missense mutation, P207S (see table 2). Login to comment 46 ABCC8 p.Val1523Ala Three different mutations were detected in proband ISPAD 81; the unaffected mother is heterozygous for the frameshift mutation c.3127ins10 and the unaffected father carries E1327K and V1523A in cis (fig. 1). Login to comment 64 ABCC8 p.Thr229Ile ABCC8 p.Thr229Ile ABCC8 p.Val1523Leu ABCC8 p.Val1523Leu Compared with homomeric A1185E or T229I/V1523L channels, the heterozygous A1185E, T229I, and V1523L channels showed greater ATP sensitivity and smaller KATP currents at 3 mM MgATP (see fig. 6). Login to comment 73 ABCC8 p.Phe132Leu ABCC8 p.Asp209Glu ABCC8 p.Thr229Ile ABCC8 p.Tyr263Asp ABCC8 p.Val1523Leu ABCC8 p.Val1523Ala ABCC8 p.Asn72Ser ABCC8 p.Val86Gly ABCC8 p.Glu382Lys ABCC8 p.Glu208Lys ABCC8 p.Phe132Val ABCC8 p.Pro207Ser ABCC8 p.Pro45Leu ABCC8 p.Tyr179* Details of ABCC8 Mutations and Clinical Information ISPAD Number Mutation (Protein Effect) Nucleotide Change Zygosity Age at Diagnosis (wk) Birth Weighta (Percentile) Neurological Feature Developmental Delay Muscle Weakness Epilepsy 123 V86Ab c.257TrC Heterozygous 8 2,900 (9) No No No 124 V86G c.257TrG Heterozygous 5 2,900 (13) No No No 68 F132Lb c.394TrC Heterozygous 13 2,200 (!1) Yes Yes Yes 125 F132L c.394TrC Heterozygous 26 2,440 (9) Yes Yes No 82 F132V c.394TrG Heterozygous 20 NA No No No 46 D209E c.627CrA Heterozygous 5 2,720 (13) No No No 134 Q211Kb c.631CrA Heterozygous 16 2,400 (3) No No No 122 L225Pc c.674TrC Heterozygous 4 2,500 (11) No No No 117 E382K c.1144GrA Homozygous 8 2,700 (4) No No No 118 A1185E c.3554CrA Homozygous 0 4,200 (95) No Yes Yes 116 N72S c.215ArG Mosaic 5 3,870 (74) No No No 47 P45L ϩ G1401R [c.134CrT] ϩ [c.4201GrA] Compound heterozygous 6 2,520 (18) Yes Yes No 119 E208K ϩ Y263D [c.622GrA] ϩ [c.787TrG] Compound heterozygous 13 2,950 (28) Yes No No 120 T229I ϩ V1523L [c.686CrT] ϩ [c.4567GrT] Compound heterozygous 4 NA No No No 78 P207S ϩ Y179X [c.619CrT] ϩ [c.536_539delATGG] Compound heterozygous 8 3,290 (29) No No No 121 [E1327K; V1523A] ϩ T1043QfsX74 [c.3979GrA; 4568CrT] ϩ [c.3127_3129delACCinsCAGCCAGGACCTG] Compound heterozygous 1 2,380 (!1) No No No a NA p not available. Login to comment 75 ABCC8 p.Leu225Pro Birth weight percentiles were calculated using population-based data,15 and, when information on gestational age was not available ( ), a gestational age of 40 wk was assumed.n p 3 b Patients ISPAD 68, 123, and 134 have been reported by us elsewhere.9,10,14 c The L225P mutation has been reported in another patient by Masia et al.8 Figure 3. Schematic representation of KATP channels in family ISPAD 78. Login to comment 76 ABCC8 p.Pro207Ser ABCC8 p.Leu225Pro The unaffected parents are heterozygous for the c.536del4 frameshift or P207S missense mutation. Login to comment 77 ABCC8 p.Pro207Ser ABCC8 p.Pro207Ser Lymphoblastoid cells showed a decrease in c.536del4 mRNA (see fig. 2), and the majority of KATP channels in the proband are predicted to be homomeric for the P207S mutation. Login to comment 78 ABCC8 p.Pro207Ser Lymphoblastoid cells showed a decrease in c.536del4 mRNA (see fig. 2), and the majority of KATP channels in the proband are predicted to be homomeric for the P207S mutation. Login to comment 94 ABCC8 p.Phe132Leu ABCC8 p.Thr229Ile ABCC8 p.Val1523Leu ABCC8 p.Pro207Ser To simulate the patient`s genotype, we coinjected Kir6.2 mRNA with hetF132L (1:1 mix of WT and F132L SUR1 mRNAs); homA1185E or P207S (mutant SUR1 only); or V1523LϩT229I (1:1 mix of V1523L and T229I SUR1). Login to comment 95 ABCC8 p.Phe132Leu ABCC8 p.Thr229Ile ABCC8 p.Val1523Leu ABCC8 p.Pro207Ser To simulate the patient`s genotype, we coinjected Kir6.2 mRNA with hetF132L (1:1 mix of WT and F132L SUR1 mRNAs); homA1185E or P207S (mutant SUR1 only); or V1523Laf9;T229I (1:1 mix of V1523L and T229I SUR1). Login to comment 102 ABCC8 p.Phe132Leu ForIC p 15 h p 1.11 n p 650 hetSUR1-F132L (a), mM, , and . Login to comment 103 ABCC8 p.Phe132Leu ABCC8 p.Pro207Ser For homSUR1-P207S (b), mM, , and . Login to comment 104 ABCC8 p.Pro207Ser For homSUR1-P207S (b), mM, , and . Login to comment 133 ABCC8 p.Phe132Leu To simulate the heterozygous state (e.g., F132L), Kir6.2 was coexpressed with a 1:1 mixture of wild-type and mutant SUR1 mRNA. Login to comment 134 ABCC8 p.Thr229Ile ABCC8 p.Val1523Leu ABCC8 p.Val1523Leu To simulate the compound heterozygous state of hetSUR1-T229IϩhetSUR1-V1523L, Kir6.2 was coexpressed with a 1:1 mixture of SUR1-T229I and SUR1-V1523L mRNAs. Login to comment 136 ABCC8 p.Phe132Leu To simulate the heterozygous state (e.g., F132L), Kir6.2 was coexpressed with a 1:1 mixture of wild-type and mutant SUR1 mRNA. Login to comment 137 ABCC8 p.Thr229Ile ABCC8 p.Val1523Leu ABCC8 p.Val1523Leu To simulate the compound heterozygous state of hetSUR1-T229Iaf9;hetSUR1-V1523L, Kir6.2 was coexpressed with a 1:1 mixture of SUR1-T229I and SUR1-V1523L mRNAs. Login to comment 154 ABCC8 p.Leu225Pro Masia R, Deleon DD, Macmullen C, McKnight H, Stanley CA, Nichols CG (2007) A mutation in the TMD0-L0 region of SUR1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Login to comment 157 ABCC8 p.Leu225Pro Masia R, Deleon DD, Macmullen C, McKnight H, Stanley CA, Nichols CG (2007) A mutation in the TMD0-L0 region of SUR1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Login to comment