ABCMdb

ABCC8 p.Asn72Ser

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Publications

PMID: 17919176 [PubMed] Patch AM et al: "Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period."

No. Sentence Comment

161 Affected probands and family members can be separated into three distinct groups based T229I/T229I ABCC8 mutations Transient Neonatal Diabetes Mellitus Recessive homozygous mutations R826W (2) H1024Y R1183Q (2) R1183W (5) R1314H R1380C (3) R1380H R1380L (2) D209E D212I D212N R306H V324M C435R L451P L582V (2) Dominant heterozygous mutations Permanent Neonatal Diabetes Mellitus E382K/E382K A1185E/A1185E Mosaic N72S Recessive homozygous or mosaic mutations P45L/G1401R E208K/Y263D T229I/V1523L L438F/M1290V P207S/c.536del4 E1327K+V1523A/ c.1327ins10 Recessive compound heterozygous mutations 1K Dominant heterozygous mutations D209E Q21 L213R L225P(2) I1425V V86A V86G F132L (2) F132V L135P Fig. 2 A diagram illustrating the inheritance of ABCC8 mutations in probands with permanent and transient forms of neonatal diabetes. Login to comment
163 Permanent Neonatal Diabetes Mellitus Transient Neonatal Diabetes Mellitus 1 5 10 15 20 25 30 35 39 N72S V86A V86G F132L F132V L135PP45L P207S E208K D209E Q211K L213R L225P T229I Y263D D209E D212I D212N T229I R306H V324M L438F L451P E382K R826W R1183W R1183Q A1185E E1327K R1314H M1290V R1380C R1380H R1380L G1401R V1523A V1523L H1024YC435R L582V I1425V Fig. 3 The location of missense mutations causing neonatal diabetes within the coding sequence of ABCC8. Login to comment
176 No neurological features were reported in R1183W/Q A1185E E1327K G1401R V1523A/L NBD1 NBD2 outside membrane inside P45L N72S F132L/V L135P P207S E208K D209E Q211K D212I/N L213R L225P T229I Y263D E382K V86A/G L438F C435R R1380C/H/L L451P R826W TMD0 TMD1 TMD2 R306H V324M L582V H1024Y I1425V R1314H M1290V Fig. 4 A schematic of the membrane topologies of SUR1 showing the location of the ABCC8 missense mutations causing neonatal diabetes. Login to comment

PMID: 17942821 [PubMed] Shield JP et al: "Mosaic paternal uniparental isodisomy and an ABCC8 gene mutation in a patient with permanent neonatal diabetes and hemihypertrophy."

No. Sentence Comment

5 RESULTS-A paternally inherited activating mutation (N72S) in the ABCC8 gene was identified in the proband. Login to comment
51 The father was identified as being heterozygous for a missense mutation, N72S (c.215AϾG), while the proband`s leukocyte DNA showed mosaicism for the N72S mutation (Fig. 2B). Login to comment
52 The N72S mutation was not found in 250 normal chromosomes, and the affected residue was conserved across species. Login to comment
53 Quantification by real-time PCR (TaqMan assay) demonstrated that the N72S mutation was present at ϳ70% in leukocyte DNA and 50% in buccal cells. Login to comment
55 Genomic DNA from the father, who is heterozygous for the N72S mutation, was used in serial dilution to produce standard curves to determine linear range and accuracy of quantification (primer and probe sequences are available on request). Login to comment
59 Functional studies in Xenopus oocytes (methods in 9,10) demonstrated that the N72S mutation results in a reduced sensitivity to inhibition by MgATP. Login to comment
60 Half-maximal block of homozygous N72S channels was produced by 23 Ϯ 1 ␮mol/l ATP (n ϭ 10) compared with 15 Ϯ 1 ␮mol/l (n ϭ 6) for wild-type channels. Login to comment
62 Homozygous N72S channels were substantially blocked by the sulfonylurea tolbutamide in vitro (Fig. 3). Login to comment
68 efficacy of sulfonylureas in neonatal diabetes caused by KATP channel mutations (21), and the tolbutamide block of mutant N72S channels observed in functional studies, prompted a trial of the sulfonylurea glyburide. Login to comment
83 The lack of a therapeutic response to sulfonyureas in our patient is puzzling, as the mutant N72S channels were blocked by tolbutamide in in vitro studies. Login to comment
94 Resting whole-cell KATP channel currents are slightly larger for homomeric N72S mutant channels and are blocked by sulfonylureas. Login to comment
95 Mean steady-state whole-cell KATP channel currents for wild-type (WT), homomeric (hom) N72S, and heterozygous (het) N72S channels, as indicated evoked by a voltage step from -10 to -30 mV before (Ⅺ, resting condition), after application of the metabolic inhibitor 3 mmol/l azide (o), and in the presence of 3 mmol/l azide plus 0.5 mmol/l tolbutamide (f). Login to comment
100 The level of mosaicism for the N72S mutation varied between leukocytes (ϳ70% mutation) and buccal cells (ϳ50% mutation). Login to comment
54 The N72S mutation was not found in 250 normal chromosomes, and the affected residue was conserved across species. Login to comment
57 Genomic DNA from the father, who is heterozygous for the N72S mutation, was used in serial dilution to produce standard curves to determine linear range and accuracy of quantification (primer and probe sequences are available on request). Login to comment
63 Half-maximal block of homozygous N72S channels was produced by 23 afe; 1 òe;mol/l ATP (n afd; 10) compared with 15 afe; 1 òe;mol/l (n afd; 6) for wild-type channels. Login to comment
65 Homozygous N72S channels were substantially blocked by the sulfonylurea tolbutamide in vitro (Fig. 3). Login to comment
71 efficacy of sulfonylureas in neonatal diabetes caused by KATP channel mutations (21), and the tolbutamide block of mutant N72S channels observed in functional studies, prompted a trial of the sulfonylurea glyburide. Login to comment
86 The lack of a therapeutic response to sulfonyureas in our patient is puzzling, as the mutant N72S channels were blocked by tolbutamide in in vitro studies. Login to comment
97 Resting whole-cell KATP channel currents are slightly larger for homomeric N72S mutant channels and are blocked by sulfonylureas. Login to comment
98 Mean steady-state whole-cell KATP channel currents for wild-type (WT), homomeric (hom) N72S, and heterozygous (het) N72S channels, as indicated evoked by a voltage step from d1a;10 to d1a;30 mV before (ǧa;, resting condition), after application of the metabolic inhibitor 3 mmol/l azide (o), and in the presence of 3 mmol/l azide plus 0.5 mmol/l tolbutamide (f). Login to comment
103 The level of mosaicism for the N72S mutation varied between leukocytes (b03;70% mutation) and buccal cells (b03;50% mutation). Login to comment

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

185 Such naturally occurring mutations TNDM PNDM DEND TNDM PNDM DEND iDEND WT P206L D212N P45L N72S P207S E208K+Y263D D212I T229I A1185E V1522L+Y229I F132L 0 0.05 0.10 0.15 fractionofcurrentremaining in3mMMgATP(a) (b) (i) (ii) Figure 4. Login to 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
188 Such naturally occurring mutations TNDM PNDM DEND TNDM PNDM DEND iDEND WT P206L D212N P45L N72S P207S E208K+Y263D D212I T229I A1185E V1522L+Y229I F132L 0 0.05 0.10 0.15 fraction of current remaining in 3 mM MgATP (a) (b) (i) (ii) Figure 4. 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: 17668386 [PubMed] Ellard S et al: "Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects."

No. Sentence Comment

35 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
73 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