ABCMdb

ABCC8 p.Val86Ala

ClinVar:	c.257T>C , p.Val86Ala D , Pathogenic
Predicted by SNAP2:	A: N (78%), C: N (78%), D: D (59%), E: N (53%), F: N (93%), G: N (57%), H: N (57%), I: N (93%), K: N (57%), L: N (93%), M: N (82%), N: N (57%), P: D (63%), Q: N (57%), R: D (53%), S: N (66%), T: N (78%), W: D (53%), Y: N (66%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: D, F: N, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: N, W: D, Y: D,

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[hide] Prevalence of permanent neonatal diabetes in Slova... J Clin Endocrinol Metab. 2007 Apr;92(4):1276-82. Epub 2007 Jan 9. Stanik J, Gasperikova D, Paskova M, Barak L, Javorkova J, Jancova E, Ciljakova M, Hlava P, Michalek J, Flanagan SE, Pearson E, Hattersley AT, Ellard S, Klimes I
Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers.
J Clin Endocrinol Metab. 2007 Apr;92(4):1276-82. Epub 2007 Jan 9., [PMID:17213273]

Abstract [show]
CONTEXT: Mutations in the KCNJ11 and ABCC8 genes encoding the pancreatic beta-cell K(ATP) channel have recently been shown to be the most common cause of permanent neonatal diabetes mellitus (PNDM). Information regarding the frequency of PNDM has been based mainly on nonpopulation or short-term collections only. Thus, the aim of this study was to identify the incidence of PNDM in Slovakia and to switch patients to sulfonylurea (SU) where applicable. DESIGN: We searched for PNDM patients in the Slovak Children Diabetes Registry. In insulin-treated patients who matched the clinical criteria for PNDM, the KCNJ11 or ABCC8 genes were sequenced, and mutation carriers were invited for replacement of insulin with SU. RESULTS: Eight patients with diabetes onset before the sixth month of life without remission were identified since 1981, which corresponds to the PNDM incidence in Slovakia of one case in 215,417 live births. In four patients, three different KCNJ11 mutations were found (R201H, H46Y, and L164P). Three patients with the KCNJ11 mutations (R201H and H46Y) were switched from insulin to SU, decreasing their glycosylated hemoglobin from 9.3-11.0% on insulin to 5.7-6.6% on SU treatment. One patient has a novel V86A mutation in the ABCC8 gene and was also substituted with SU. CONCLUSIONS: PNDM frequency in Slovakia is much higher (one in 215,417 live births) than previously suggested from international estimates (about one in 800,000). We identified one ABCC8 and four KCNJ11 mutation carriers, of whom four were successfully transferred to SU, dramatically improving their diabetes control and quality of life.

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8 One patient has a novel V86A mutation in the ABCC8 gene and was also substituted with SU. Login to comment
108 SK-1 SK-2 SK-3 SK-4 SK-5 SK-6 SK-7 SK-8 Diagnosis KCNJ11 mutation R201H KCNJ11 mutation L164P, VHC PNDM, unknown etiologya KCNJ11 mutation H46Y Wolcott-Rallison syndrome KCNJ11 mutation R201H Intermediate DEND, not analyzed ABCC8 mutation V86A Gender Female Female Male Female Male Male Female Male Birth weight (g) 3000 2600 2450 3500 3750 2480 1450 2900 Gestation (wk) 39 40 40 40 42 40 37 40 DM onset (wk) 18 5 10 15 11 4 Ͻ1 9 Dysmorphic features No No No Mild No No Yes No Seizures No No No No No No No No Developmental delay No No No No No No Yes No Autoantibodies Negative Negative Negative Negative Negative Negative Negative Negative Therapy after onset Insulin Insulin Insulin Insulin Insulin Insulin Insulin Insulin Insulin (IU/kg⅐d) 0.6 1.24 0.8 1 0.8 0.66 0.5 0.45 C-peptide (ng/ml) 0.01 0.01 0.42 0.04 0.18 0.11 0.12 0.01 Current status Current age (yr) 25 19 13 12 11 11 Deceased at 18 months 5 Current therapy SU Insulin Insulin SU Insulin SU Insulin SU Current HbA1c (%) 7.0 15.2 12.2 6.6 15.1 5.7 Not available 6.9 DM, Diabetes mellitus; VHC, virus hepatitis C. a Negative for mutations in KCNJ11, SUR1, IPF1, and NEUROD1 genes. Login to comment
111 V86A (c.257TϾC) is a novel mutation in exon 2 of the ABCC8 gene that results in the substitution of alanine for valine at codon 86 (p.Val86Ala). Login to comment
118 Clinical characteristics of the ABCC8 mutation carrier Patient SK-8 with the V86A mutation was born in the 40th gestational week with birth weight of 2800 g and developed diabetes in his second month of life as manifested with polyuria, polydipsia, and failure to thrive during a respiratory tract infection. Login to comment

[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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85 Five residues are sites for different amino acid substitutions: V86A/G, F132L/V, D212I/N, R1183Q/W and R1380C/H/L. Login to 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
197 Genotype-phenotype Correlation Most of the dominantly acting mutations located in exons 2-5 of the ABCC8 gene (V86A/G, F132L/V, L135P, D209E, Q211K, L213R and L225P) cause PNDM. Login to comment
224 Furthermore, different mutations at the same residue (V86A/G, F132L/V, D212I/N, R1183Q/W and R1380C/H/L) cause either PNDM (V86 and F132) or biphasic TNDM (D212, R1183 and R1380), suggesting a different pathological mechanism. 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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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

[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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54 Doses Table 1-Clinical characteristics of patients with SUR1 mutations according to success of treatment with sulfonylureas Characteristic All patients Patients with successful sulfonylurea treatment Patients with unsuccessful sulfonylurea treatment P* n 27 23 4 Mutation (number of patients) NA V86G†, P45L/G1401R- (2)†, D209E (3)†, T229I/V1523L†, Q211K†, V86A (2)†, E1507G, V215I/V607M, E208K/Y263D†, R1380L (2)‡, D212I (3)§, T229I/T229I‡, R1183W§, L225P†, R826W, and D209N F132L (2)†, F132V†, and N72S† (mosaic). Login to comment
56 Doses Table 1-Clinical characteristics of patients with SUR1 mutations according to success of treatment with sulfonylureas Characteristic All patients Patients with successful sulfonylurea treatment Patients with unsuccessful sulfonylurea treatment P* n 27 23 4 Mutation (number of patients) NA V86Gߤ, P45L/G1401R- (2)ߤ, D209E (3)ߤ, T229I/V1523Lߤ, Q211Kߤ, V86A (2)ߤ, E1507G, V215I/V607M, E208K/Y263Dߤ, R1380L (2)ߥ, D212I (3)&#a7;, T229I/T229Iߥ, R1183W&#a7;, L225Pߤ, R826W, and D209N F132L (2)ߤ, F132Vߤ, and N72Sߤ (mosaic). Login to comment

[hide] Personalized medicine switching from insulin to su... Diagn Mol Pathol. 2012 Mar;21(1):56-9. Mak CM, Lee CY, Lam CW, Siu WK, Hung VC, Chan AY
Personalized medicine switching from insulin to sulfonylurea in permanent neonatal diabetes mellitus dictated by a novel activating ABCC8 mutation.
Diagn Mol Pathol. 2012 Mar;21(1):56-9., [PMID:22306677]

Abstract [show]
BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare but important condition affecting approximately 1 in 100,000 newborns. Permanent form requires life-long treatment with difficulties in long-term compliance and metabolic complications. Exact genetic diagnosis can enable improved outcome and patient satisfaction by switching insulin injection to oral sulfonylureas. Successful cases have been reported with most experience on the KCNJ11-mutated permanent form. Here we report a successful experience in an ABCC8-mutated infant with permanent NDM. PATIENT AND METHODS: A 4-month-old Chinese girl was incidentally found to have hyperglycemia with baseline C-peptide of 0.05 nmol/L requiring insulin injection of 0.2 IU/kg/d. Genetic analysis of KCNJ11 and ABCC8 was performed by polymerase chain reaction and direct DNA sequencing at the age of 3 years. Sulfonylurea transition was conducted after the ABCC8 mutation detection. RESULTS: A novel homozygous ABCC8 NM_000352.3: c.3068 A>G; NP_000343.2: p.H1023R mutation was detected. C-peptide level increased to 0.14 nmol/L and HbA1c was normalized to 5.8% from 8.0% after 8 months of oral glibenclamide treatment with a maintenance dosage of 0.65 mg/kg/d. CONCLUSIONS: In this patient with ABCC8-mutated permanent NDM, oral sulfonylurea is also effective in achieving satisfactory diabetic control. Our study adds information to the personalized medicine practice of ABCC8-mutated permanent NDM.

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33 The last patient carried a heterozygous mutation (p.V86A) in ABCC8 with baseline C-peptide of 0.003nmol/L and initially required insulin of 0.45 IU/kg/d. 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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7 Results We identified two probands with permanent ND (one heterozygousF132Vmutationcarrierandonecompoundheterozygote with N23H and R826W mutations) and two others with relapsed transient ND (heterozygotes for R826W and V86A substitutions, respectively). Login to comment
10 The C-peptide level varied from 0Æ1 ng/ml (F132V) to 0Æ75 ng/ml (V86A). Login to comment
14 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. 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
38 Two probands had relapsed transient diabetes (V86A and R826W heterozygotes). Login to comment
39 The patient with the V86A mutation was treated with insulin from diagnosis until the age of 6 years when she stopped treatment for 2 years. Login to comment
46 Microsatellite analysis confirmed that the F132V and V86A mutations had arisen de novo. Login to comment
51 The C-peptide level varied from 0Æ1 ng/ml (F132V) to 0Æ75 ng/ml (V86A). Login to comment
55 This was fully successful in probands with R826W and V86A mutations (Families B and C, respectively). Login to comment
60 All examined auto-antibodies were present in high concentration in one diabetic mutation carrier, a 16-year-old girl with the V86A substitution. Login to comment
65 The girl with the V86A mutation carried DRB1*1501-DQA1*0102- DQB1*0602 and DRB1*11-DQA1*0501-DQB1*0301 haplotypes, one of them associated with strong and one with moderate protection from T1DM.21 Discussion We report here the results of a search for subjects with neonatal diabetes due to mutations in the ABCC8 gene in a cohort of patients from Poland. 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
82 One notable exception is a patient with the most common PNDM Kir6Æ2 mutation R201H who experienced a 5-years remission period.24 In our study the patient with the V86A mutation had a period of remission between the age of 6 and 8 years and was therefore classified as relapsed TNDM. Login to comment
93 The frequency of positive ICAs and ICA in the general population of children and adolescence may reach 4Æ1% and 2Æ0% as earlier reported, respectively.26 The presence of all three positive autoantibodies, like in the carrier of the V86A mutation, was very rare (< 1/ 1000) and it was associated with progression to T1DM in individuals with predisposing HLA haplotypes. 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