ABCMdb

ABCC8 p.Phe132Val

ClinVar:	c.394T>G , p.Phe132Val D , Pathogenic/Likely pathogenic
Predicted by SNAP2:	A: D (53%), C: N (72%), D: D (80%), E: D (75%), G: D (63%), H: D (59%), I: N (57%), K: D (75%), L: N (66%), M: N (61%), N: D (71%), P: D (75%), Q: D (66%), R: D (66%), S: D (53%), T: N (57%), V: N (57%), W: N (57%), Y: N (78%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: N, G: D, H: N, I: N, K: N, L: N, M: N, N: D, P: D, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] Mutations in the ABCC8 gene encoding the SUR1 subu... Diabetes Obes Metab. 2007 Nov;9 Suppl 2:28-39. Patch AM, Flanagan SE, Boustred C, Hattersley AT, Ellard S
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.
Diabetes Obes Metab. 2007 Nov;9 Suppl 2:28-39., [PMID:17919176]

Abstract [show]
AIM: Mutations in the ABCC8 gene encoding the SUR1 subunit of the pancreatic ATP-sensitive potassium channel cause permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). We reviewed the existing literature, extended the number of cases and explored genotype-phenotype correlations. METHODS: Mutations were identified by sequencing in patients diagnosed with diabetes before 6 months without a KCNJ11 mutation. RESULTS: We identified ABCC8 mutations in an additional nine probands (including five novel mutations L135P, R306H, R1314H, L438F and M1290V), bringing the total of reported families to 48. Both dominant and recessive mutations were observed with recessive inheritance more common in PNDM than TNDM (9 vs. 1; p < 0.01). The remainder of the PNDM probands (n = 12) had de novo mutations. Seventeen of twenty-five children with TNDM inherited their heterozygous mutation from a parent. Nine of these parents had permanent diabetes (median age at diagnosis: 27.5 years, range: 13-35 years). Recurrent mutations of residues R1183 and R1380 were found only in TNDM probands and dominant mutations causing PNDM clustered within exons 2-5. CONCLUSIONS: ABCC8 mutations cause PNDM, TNDM or permanent diabetes diagnosed outside the neonatal period. There is some evidence that the location of the mutation is correlated with the clinical phenotype.

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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
184 a third patient with a different mutation at the same residue (F132V). Login to comment

[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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57 For example the R50Q KCNJ11 mutation and the F132V ABCC8 mutation cause isolated diabetes whilst the R50P and F132L mutations cause DEND syndrome [22, 27, 40]. Login to comment

[hide] Effective treatment with oral sulfonylureas in pat... Diabetes Care. 2008 Feb;31(2):204-9. Epub 2007 Nov 19. Rafiq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley AT
Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations.
Diabetes Care. 2008 Feb;31(2):204-9. Epub 2007 Nov 19., [PMID:18025408]

Abstract [show]
OBJECTIVE: Neonatal diabetes can result from mutations in the Kir6.2 or sulfonylurea receptor 1 (SUR1) subunits of the ATP-sensitive K(+) channel. Transfer from insulin to oral sulfonylureas in patients with neonatal diabetes due to Kir6.2 mutations is well described, but less is known about changing therapy in patients with SUR1 mutations. We aimed to describe the response to sulfonylurea therapy in patients with SUR1 mutations and to compare it with Kir6.2 mutations. RESEARCH DESIGN AND METHODS: We followed 27 patients with SUR1 mutations for at least 2 months after attempted transfer to sulfonylureas. Information was collected on clinical features, treatment before and after transfer, and the transfer protocol used. We compared successful and unsuccessful transfer patients, glycemic control before and after transfer, and treatment requirements in patients with SUR1 and Kir6.2 mutations. RESULTS: Twenty-three patients (85%) successfully transferred onto sulfonylureas without significant side effects or increased hypoglycemia and did not need insulin injections. In these patients, median A1C fell from 7.2% (interquartile range 6.6-8.2%) on insulin to 5.5% (5.3-6.2%) on sulfonylureas (P = 0.01). When compared with Kir6.2 patients, SUR1 patients needed lower doses of both insulin before transfer (0.4 vs. 0.7 units x kg(-1) x day(-1); P = 0.002) and sulfonylureas after transfer (0.26 vs. 0.45 mg x kg(-1) x day(-1); P = 0.005). CONCLUSIONS: Oral sulfonylurea therapy is safe and effective in the short term in most patients with diabetes due to SUR1 mutations and may successfully replace treatment with insulin injections. A different treatment protocol needs to be developed for this group because they require lower doses of sulfonylureas than required by Kir6.2 patients.

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75 Two of these patients with F132V and F132L mutations had increased C-peptide levels following the transfer, but it was decided that the response was insufficient to discontinue insulin. Login to comment
77 Two of these patients with F132V and F132L mutations had increased C-peptide levels following the transfer, but it was decided that the response was insufficient to discontinue insulin. Login to comment

[hide] Mutations in the ABCC8 (SUR1 subunit of the K(ATP)... Clin Endocrinol (Oxf). 2009 Sep;71(3):358-62. Epub 2008 Nov 18. Klupa T, Kowalska I, Wyka K, Skupien J, Patch AM, Flanagan SE, Noczynska A, Arciszewska M, Ellard S, Hattersley AT, Sieradzki J, Mlynarski W, Malecki MT
Mutations in the ABCC8 (SUR1 subunit of the K(ATP) channel) gene are associated with a variable clinical phenotype.
Clin Endocrinol (Oxf). 2009 Sep;71(3):358-62. Epub 2008 Nov 18., [PMID:19021632]

Abstract [show]
OBJECTIVE: Mutations in the ABCC8 gene encoding the SUR1 subunits of the beta-cell K-ATP channel cause neonatal diabetes (ND) mellitus. We aimed to determine the contribution of ABCC8 gene to ND in Poland, to describe the clinical phenotype associated with its mutations and to examine potential modifying factors. PATIENTS: The Nationwide Registry of ND in Poland includes patients diagnosed before 6 months of age. In total 16 Kir6.2 negative patients with ND, 14 permanent and 2 relapsed transient, were examined. MEASUREMENTS: ABCC8 gene mutations were detected by direct sequencing. Mutation carriers' characteristics included clinical data and biochemical parameters. In addition, we performed the hyperinsulinaemic euglycaemic clamp and tested for islet-specific antibodies in diabetic subjects. RESULTS: We identified two probands with permanent ND (one heterozygous F132V mutation carrier and one compound heterozygote with N23H and R826W mutations) and two others with relapsed transient ND (heterozygotes for R826W and V86A substitutions, respectively). One subject, a heterozygous relative with the R826W mutation, had adult onset diabetes. There were striking differences in the clinical picture of the mutation carriers as the carrier of two mutations, N23H and R826W, was controlled on diet alone with HbA(1c) of 7.3%, whereas the F132V mutation carrier was on 0.66 IU/kg/day of insulin with HbA(1c) of 11.7%. The C-peptide level varied from 0.1 ng/ml (F132V) to 0.75 ng/ml (V86A). We also observed a variable insulin resistance, from moderate (M = 5.5 and 5.6 mg/kg/min, respectively, in the two R826W mutation carriers) to severe (M = 2.6 mg/kg/min in the F132V mutation carrier). We were able to transfer two patients off insulin to sulphonylurea (SU) and to reduce insulin dose in one other patient. Interestingly, there was no response to SU in the most insulin resistant F132V mutation carrier despite high dose of glibenclamide. All examined auto-antibodies were present in one of the subjects, the V86A mutation carrier, although this did not seem to influence the clinical picture, as we were able to transfer this girl off insulin. CONCLUSION: Mutations in SUR1 are the cause of about 15% of Kir6.2 negative permanent ND in Poland. The clinical phenotype of SUR1 diabetic mutation carriers is heterogeneous and it appears to be modified by variable sensitivity to insulin.

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9 There were striking differences in the clinical picture of the mutation carriers as the carrier of two mutations, N23H and R826W, was controlled on diet alone with HbA1c of 7Æ3%, whereas the F132V mutation carrier was on 0Æ66 IU/ kg/day of insulin with HbA1c of 11Æ7%. Login to comment
10 The C-peptide level varied from 0Æ1 ng/ml (F132V) to 0Æ75 ng/ml (V86A). Login to comment
11 We also observed a variable insulin resistance, from moderate (M ¼ 5Æ5 and 5Æ6 mg/kg/ min, respectively, in the two R826W mutation carriers) to severe (M ¼ 2Æ6 mg/kg/min in the F132V mutation carrier). Login to comment
13 Interestingly, there was no response to SU in the most insulin resistant F132V mutation carrier despite high dose of glibenclamide. Login to comment
34 Three were heterozygous carriers of the F132V (c.394T > G; p.Phe132Val), R826W (c.2476T > C; p.Arg826Trp) and V86A (c.257T > C; p.Val86Ala) substitutions; one patient was a compound heterozygote who carried two, N23H (c.67 A > C; p.Asn23His) and R826W, mutations in trans. Login to comment
35 The patient with the F132V mutation was included in a previous publication,18 R826W has previously been reported in two probands with TNDM,2,19 V86A was identified in a Slovakian patient with PNDM,20 but N23H is novel. Login to comment
44 Both he and the F132V mutation carrier who has been treated with insulin since the age of 5 months were classified as having PNDM. Login to comment
46 Microsatellite analysis confirmed that the F132V and V86A mutations had arisen de novo. Login to comment
50 There were striking differences in the clinical picture of SUR1 related diabetes as, for example, the compound heterozygote was controlled on diet alone with HbA1c of 7Æ3%, while the F132V mutation carrier wason47unitsof insulin/daywith HbA1c of 11Æ7%. Login to comment
51 The C-peptide level varied from 0Æ1 ng/ml (F132V) to 0Æ75 ng/ml (V86A). Login to comment
53 Interestingly, there was some evidence of a variable degree of resistance to insulin: from moderate (M ¼ 5Æ5 and 5Æ6 mg/kg/min, respectively, in two R826W mutation carriers) to severe (M ¼ 2Æ6 mg/kg/min in the F132V mutation carrier). Login to comment
59 There was no clinical response to SU treatment in the most insulin resistant F132V carrier of the mutation despite 6 months of high dose SUs (> 1 mg/kg/day of glibenclamide, with a maximum dose of 1Æ5 mg/kg/day). Login to comment
66 The causative relationships between both de novo variants, V86A and F132V, and diabetic phenotype are evident, particularly as different mutations at these residues (F132L and V86G) were previously described in other cases of neonatal diabetes4,18 in addition to another case of PNDM with the V86A mutation.20 The R826W mutation was found in two families in this study but they are not known to share a common ancestor. Login to comment
79 No neurological symptoms were present in all identified ABCC8 gene mutation carriers, including the patient with the F132V substitution. Login to comment
86 Forexample, a woman with the most severe diabetes, the carrier of the F132V mutation who failed to respond to SU, also had the largest degree of resistance to insulin. Login to comment
98 Clinical characteristics of diabetic ABCC8 mutation carriers Patient`s number and ABCC8 mutation Treatment at the study entry Neurological symptoms Diabetic complications Current treatment BMI (kg/m2 ) C-peptide (ng/ml) HbA1c (%) M [mg/ (kg· min)] Positive autoantibodies Pol6-1 F132V Insulin- 0Æ66 IU/kg/day Not present Diabetic retinopathy Insulin 1Æ19 IU/kg/day 21Æ7 22Æ4 0Æ1 11Æ7 12Æ0 2Æ6 N/A None Pol10-1 V86A Insulin- 0Æ77 IU/kg/day Not present None Glipizide GITS 20 mg/day 21Æ5 21Æ5 0Æ7 2Æ2 12Æ2 5Æ8 N/A N/A ICA, GADA, IA2-Ab Pol20-1 Insulin 0Æ37 IU/kg/day Not present None Glipizide GITS 22Æ53 0Æ66 6Æ5 5Æ6 None R826W 10 mg/day 23Æ45 2Æ07 5Æ4 8Æ73 Pol20-3 Insulin 0Æ40 IU/kg/day Not present None Glibenclamide 45 mg/day 21Æ0 0Æ39 8Æ5 5Æ5 None R826W Insulin 0Æ20 IU/kg/day 19Æ7 0Æ37 7Æ7 6Æ5 Pol29-1 Diet Not present None Diet 13Æ8 0Æ16 7Æ3 N/A IA2-Ab R826W/N23H 16Æ1 7Æ2 N/A For BMI, C-peptide, HbA1c and M parameter we provided the initial data and the results obtained during the re-examination performed at the 3 month for all patients, but Pol6-1 (6 months). Login to comment

[hide] Permanent neonatal diabetes caused by dominant, re... Am J Hum Genet. 2007 Aug;81(2):375-82. Epub 2007 Jun 29. 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., [PMID:17668386]

Abstract [show]
Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.

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27 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
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