ABCC8 p.Arg598*
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[hide] Histopathology of congenital hyperinsulinism: retr... Pediatr Dev Pathol. 2003 Jul-Aug;6(4):322-33. Suchi M, MacMullen C, Thornton PS, Ganguly A, Stanley CA, Ruchelli ED
Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations.
Pediatr Dev Pathol. 2003 Jul-Aug;6(4):322-33., [PMID:14692646]
Abstract [show]
The majority of the most severe cases of congenital hyperinsulinism (HI) are caused by defects in the beta-cell adenosine triphosphate (ATP)-sensitive potassium channel and usually require pancreatectomy to control blood sugar levels. In contrast to the recent advances in understanding the pathophysiology and genetic bases of HI, the histologic classification of this condition remains controversial. A recent proposal to classify the HI pancreata into diffuse and focal forms has drawn much interest because of its relative simplicity and its good correlation with the genetic abnormalities. We undertook a retrospective study to determine whether this classification scheme could be applied to 38 pancreata resected for HI at our institution. We also obtained leukocyte genomic DNA from 29 cases and screened the exons of ABCC8 and KCNJ11 genes for the presence of mutations. Nineteen cases (50.0%) were histologically classified as diffuse HI and 14 cases (36.8%) were categorized as focal form. The mutational analysis revealed that 14 of the 16 diffuse cases analyzed had either homozygous or compound heterozygous mutations of ABCC8 or KCNJ11 and 7 of 10 focal cases had only the paternally inherited mutations, consistent with the previous observations. Two patients (5.3%) had normal pancreatic histology but had persistent hypoglycemia postoperatively, leaving the possibility of residual focal lesion. Three of 38 cases (7.9%) did not fit well into either diffuse or focal category. Two cases differed from the described pattern for the diffuse form in that the nuclear enlargement was confined to a single area of the pancreas. The other case had a focal lesion but beta-cell nuclear enlargement was present in nonadjacent areas. Mutations for typical diffuse or focal HI were not identified in two of these three equivocal cases. We conclude from this study that nearly 90% of HI cases can be classified into either a diffuse or a focal form. However, a small percentage of cases represented a diagnostic challenge.
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148 Clinical features, histologic diagnoses, and genotypes of HI patients Case no. Sex Age at surgery Type of pancreatectomy Immediate outcome Histology ABCC8 and KCNJ11 mutations (paternal/ maternala ) 1 F Newborn Near total Hypoglycemia Diffuse 3992-9 g to a/delF1388 2 F 5 m, 28 d Near total Hypoglycemia Diffuse ND 3 M 1 m, 14 d Near total Hypoglycemia Diffuse 3992-9 g to a/R1215Q 4 F 1 m, 6 d Near total Hypoglycemia Diffuse delF1388/3992-9 g to a 5 F 0 m, 28 d Near total Hypoglycemia Diffuse 3992-9 g to a/3992-9 g to a 6 M 0 m, 14 d Near total Hypoglycemia Diffuse 3992-9 g to a/delF1388 7 M 0 m, 17 d Near total Diabetes mellitus Diffuse 3992-9 g to a/3992-9 g to a 8 M 1 y, 11 m Near total Hypoglycemia Diffuse -/- 9 M 1 y, 2 m Near total Hypoglycemia Diffuse 3992-9 g to a/3992-9 g to a 10 M 1 m, 17 d Near total Hypoglycemia Diffuse ND 11 M 0 m, 27 d Near total Hypoglycemia Diffuse 3992-9 g to a/3992-9 g to a 12 F 1 m, 10 d Near total Hypoglycemia Diffuse ND 13 M 1 m, 3 d Partial Hypoglycemia Diffuse delF1388/3992-9 g to a 2 m, 24 d Partial Hypoglycemia Diffuse 2 y, 6 m Near total Hypoglycemia Diffuse 14 F 1 m, 7 d Near total Hypoglycemia Diffuse delF1388/3992-9 g to a 15 M 0 m, 16 d Near total Hypoglycemia Diffuse 3992-9 g to a/3992-9 g to a 16 F 1 y, 8 m Near total Hypoglycemia Diffuse -/- 17 F 4 m, 19 d Near total Diabetes mellitus Diffuse * G134Ab /* P266Lb 18 M 1 m, 5 d Near total Diabetes mellitus Diffuse * R74W/R1215Q 19 F 3 m, 27 d Near total Hypoglycemia Diffuse * R999X/* R598X 20 F Infant Near total Cure Focal ND 21 F 1 m, 16 d Near total Cure Focal ND 22 M 0 m, 13 d Near total Cure Focal ND 23 M 1 m, 7 d Near total Hypoglycemia Focal * 2116 ϩ 1 g to t (not maternal) 24 M 1 m, 26 d Near total Cure Focal ND 25 M 0 m, 15 d Near total Cure Focal 3992-9 g to a/- 26 M 1 m, 30 d Near total Cure Focal R1494Q/- 27 F 7 m, 24 d Near total Cure Focal -/- 28 M 0 m, 27 d 95% Hypoglycemia Normal 3992-9 g to a/- 1 m, 18 d Near total Hypoglycemia Focal 29 M 1 m, 27 d Near total Hypoglycemia Focal * 3576del g/- 2 m, 0 d Near total Hypoglycemia 2 m, 18 d Total Hypoglycemia 30 M 2 m, 28 d Near total Cure Focal * R74W/- 31 M 1 m, 2 d Near total Hypoglycemia Focal * C717X/- 32 F 1 m, 22 d Near total Cure Focal * 1874del c/- 33 M 2 m, 16 d 30% Cure Focal Q954X/- 34 F 2 m, 7 d 85% Hypoglycemia Normal ND 3 m, 4 d Near total Hypoglycemia Normal (continued) the patient underwent a mere 30% pancreatectomy.
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ABCC8 p.Arg598* 14692646:148:1503
status: NEW172 Patient no. 19 was compound heterozygous for two novel nonsense mutations, R999X and R598X (Table 3), also consistent with a diffuse disease.
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ABCC8 p.Arg598* 14692646:172:85
status: NEW[hide] Genotype-phenotype correlations in children with c... J Clin Endocrinol Metab. 2005 Feb;90(2):789-94. Epub 2004 Nov 23. Henwood MJ, Kelly A, Macmullen C, Bhatia P, Ganguly A, Thornton PS, Stanley CA
Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes.
J Clin Endocrinol Metab. 2005 Feb;90(2):789-94. Epub 2004 Nov 23., [PMID:15562009]
Abstract [show]
Congenital hyperinsulinism (HI) is most commonly caused by recessive mutations of the pancreatic beta-cell ATP-sensitive potassium channel (K(ATP)), encoded by two genes on chromosome 11p, SUR1 and Kir6.2. The two mutations that have been best studied, SUR1 g3992-9a and SUR1 delF1388, are null mutations yielding nonfunctional channels and are characterized by nonresponsiveness to diazoxide, a channel agonist, and absence of acute insulin responses (AIRs) to tolbutamide, a channel antagonist, or leucine. To examine phenotypes of other K(ATP) mutations, we measured AIRs to calcium, leucine, glucose, and tolbutamide in infants with recessive SUR1 or Kir6.2 mutations expressed as diffuse HI (n = 8) or focal HI (n = 14). Of the 24 total mutations, at least seven showed evidence of residual K(ATP) channel function. This included positive AIR to both tolbutamide and leucine in diffuse HI cases or positive AIR to leucine in focal HI cases. One patient with partial K(ATP) function also responded to treatment with the channel agonist, diazoxide. Six of the seven patients with partial defects had amino acid substitutions or insertions; whereas, the other patient was compound heterozygous for two premature stop codons. These results indicate that some K(ATP) mutations can yield partially functioning channels, including cases of hyperinsulinism that are fully responsive to diazoxide therapy.
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54 Gene Haplotype Calcium (U/ml) Leucine (U/ml) Glucose (U/ml) Tolbutamide (U/ml) Diazoxide responsive Diffuse HI 1 SUR1 delF1388/D1472H 6 2 13 -2 No 2 Kir6.2 G134A/P266L 20 3 36 -2 No 3 SUR1 g3992-9a/g1630ϩ1a 11 16 -2 No 4 SUR1 N188S/D1472N 7 1 7 7 No 5 SUR1 R598X/R999X 32 1 72 27 No 6 SUR1 R495Q/R1215Q -2 15 44 30 No 7 SUR1 R74W/R1215Q 52 28 20 98 No 8 SUR1 g3992-9a/K1337N 2 18 39 33 Yes Focal HI 9 SUR1 F27S 17 -1 16 29 No 10 SUR1 F686S 12 2 27 12 No 11 SUR1 E501K 6 3 9 10 No 12 SUR1 3576delg 9 6 9 12 No 13 SUR1 g3992-9a 5 8 25 9 No 14 SUR1 g3992-9a 3 8 40 21 No 15 SUR1 c2924-10a 4 8 67 29 No 16 Kir6.2 A101D 1 8 177 88 No 17 SUR1 R1215W 7 9 15 6 No 18 Kir6.2 R136L 8 10 115 21 No 19 SUR1 g3992-9a 40 15 35 -0.3 No 20 SUR1 6aa insertion in exon 5 6 16 22 15 No 21 SUR1 R1215W 38 47 58 15 No 22 Kir6.2 R301H 16 55 75 14 No Controls (U/ml, mean Ϯ SD) KATP HI (n ϭ 7) 28 Ϯ 16 5 Ϯ 8 12 Ϯ 9 4 Ϯ 6 No GDH-HI (n ϭ 7) 2.3 Ϯ 5.4 42 Ϯ 27 120 Ϯ 52 94 Ϯ 56 Yes Normal (n ϭ 6) 3 Ϯ 4 1.4 Ϯ 2.8 56 Ϯ 26 48 Ϯ 32 Yes a To convert insulin (U/ml to pmol/liter), multiply by 6.0. identified in other patients.
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ABCC8 p.Arg598* 15562009:54:295
status: NEW107 Degree of residual channel function in KATP mutations Null Indeterminate Partial SUR1 g3992-9a g1630ϩ1a R598X/R999X delF1388 N188S/D1472N R495Q/R1215Q F27S 3576delg R74W/R1215Q F686S K1337N E501K 6 aa insertion in exon 5 c2924-10a R1215W Kir6.2 G134A/P266L R301H A101D R136L FIG. 1.
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ABCC8 p.Arg598* 15562009:107:110
status: NEW[hide] The Knudson's two-hit model and timing of somatic ... J Clin Endocrinol Metab. 2006 Oct;91(10):4118-23. Epub 2006 Aug 1. Giurgea I, Sempoux C, Bellanne-Chantelot C, Ribeiro M, Hubert L, Boddaert N, Saudubray JM, Robert JJ, Brunelle F, Rahier J, Jaubert F, Nihoul-Fekete C, de Lonlay P
The Knudson's two-hit model and timing of somatic mutation may account for the phenotypic diversity of focal congenital hyperinsulinism.
J Clin Endocrinol Metab. 2006 Oct;91(10):4118-23. Epub 2006 Aug 1., [PMID:16882742]
Abstract [show]
BACKGROUND: Congenital hyperinsulinism (CHI) is associated with focal hyperplasia of endocrine tissue in 40-65% of patients. Focal CHI is sporadic and is caused by a germline, paternally inherited, mutation of the SUR1 (ABCC8) or KIR6.2 (KCNJ11) genes (encoding subunits of the pancreatic ATP-dependent potassium channel) together with somatic maternal haploinsufficiency for 11p15.5. Plurifocal or large forms of focal CHI are a cause of apparent failure of surgery, and their underlying mechanism has not been thoroughly investigated. PATIENTS: We here report two patients with bifocal CHI as evidenced by relapsing hypoglycemia after removal of the first focal lesion and the detection of a second, distinct, focal adenomatous hyperplasia during later surgery (patients 1 and 2) and a patient with a giant focal lesion involving the major part of the pancreas (patient 3). RESULTS: In the three patients, a germline, paternally inherited, mutation of SUR1 was found. In patients 1 and 2, haploinsufficiency for the maternal 11p15.5 region resulted from a somatic deletion specific for each of the focal lesions, as shown by the diversity of deletion break points. In patient 3, an identical somatic maternal 11p15 deletion demonstrated by similar break points was shown in two independent lesion samples, suggesting a very early event during pancreas embryogenesis. CONCLUSION: Individual patients with focal hyperinsulinism may have more than one focal pancreatic lesion due to separate somatic maternal deletion of the 11p15 region. These patients and those with solitary focal lesions may follow the two-hit model described by Knudson. The stage of embryogenesis at which the somatic event occurs may account for the observed histological diversity (early event giant lesion, later event small lesion).
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83 In addition, all three patients had a heterozygous, paternally inherited SUR1 (ABCC8) gene mutation (patient 1, c.3988 ϩ 2_ϩ15del14; patient 2, R598X; patient 3, P1413L).
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ABCC8 p.Arg598* 16882742:83:156
status: NEW[hide] Mutation spectra of ABCC8 gene in Spanish patients... Hum Mutat. 2006 Feb;27(2):214. Fernandez-Marmiesse A, Salas A, Vega A, Fernandez-Lorenzo JR, Barreiro J, Carracedo A
Mutation spectra of ABCC8 gene in Spanish patients with Hyperinsulinism of Infancy (HI).
Hum Mutat. 2006 Feb;27(2):214., [PMID:16429405]
Abstract [show]
Hyperinsulinism of Infancy (HI) is a clinical disorder characterized by deregulation of insulin secretion that leads to profound hypoglycemia. Mutations in genes encoding the ATP-regulated potassium channels of the pancreatic beta-cell, namely ABCC8 (SUR1) and KCNJ11 (Kir6.2), are the major genetic known cause of the disease. To elucidate the genetic etiology of HI in the uncharacterized Spanish population, we conducted extensive sequencing analysis of the ABCC8 (83.5Kb) and KCNJ11 (1.7Kb) genes in 34 Spanish HI patients. Mutations in ABCC8 were detected for both alleles in 13 patients, while ten patients carried only one mutation in one of the ABCC8 alleles. We have detected 22 novel and seven previously described mutations in ABCC8, approximately 60% of them lead to a premature termination signal, which would result in truncated SUR1 proteins. No mutations were found in the KCNJ11 gene. In addition, we report for the first time a 3914bp macrodeletion associated with the HI disorder. The potential pathogenicity of several additional variants is discussed. The spatial pattern of three pathological mutations suggests possible geographical founder effects. This work reveals for first time the involvement of KATP channels in the pathogenesis of an important proportion (approximately 68%) of Spanish HI patients. The spectrum of mutations in Spanish HI patients provides an important tool for diagnosis and prognosis of HI patients in the Spanish population, as well as for genetic counseling of HI families.
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137 Clinical characteristics of HI Spanish patients that carry at least one mutation in ABCC8 Mutationsg Pa Ob Sex Mc Td PCe PTf Pchrh Mchrh 1a Gal M >p90 DZ 5 (>90%) OT, NF, GC p.R248X c.3576delG 1b Gal F >p50 DZ, OT, NF - OT, NF, NGT p.R248X c.3576delG 3 Gal F >p90 DZ 2 (95%) - c.584 585insA c.584 585insA 4 Gal M >p75 DZ 4 (95%) DZ, NGT c.584 585insA c.584 585insA 5 Gal M >p50 OT, DZ 16 (90%) - c.1347 1348delGA - 8 Cast M >p75 DZ, OT, GC - - p.M233R - 9 Cast F >p75 DZ 0.5 (85%) DZ, OT, PC (99%) p.G111R - 12 And M - - - - c.4612 -2 A>T p.D310N 14 Cat M >p75 DZ - - p.R934X c.3992-9 G>A 17 Cat F >p90 DZ, OT - - c.3133 3152del c.4619 4620insT 18 Cat M <p50 DZ, CNF 0.5 (95%) DZ c.1732 1746dup - 19 Can M <p50 DZ, NF, OT 2 (99%) - c.1332+4438 1631-9207del c.1332+4438 1631-9207del 20 Cat M - DZ, NF, GC - - c.2142delG p.T1131P 21 Cat F >p50 DZ, NF - - - i - i 23 Bal M >p90 CNF - - c.4310 G>A c.1732 1746dup 25 Mor M - DZ, OT yes (EXITUS) p.N188S, c.4123-19 C>T p.N188S, c.4123-19 C>T 27 Cast F >p75 DZ, CNF 24 (75%) PC (99%) p.R598X p.L1451P 28 Cat M >p90 DZ, CNF - - p.R1251X p.L1148R 30 Cast M >p90 DZ, OT 5 (95%) DZ, OT (EXITUS) p.R74W - 31 Gal F >p90 DZ 0.5 (95%) DZ - p.K719T 32 Cat F >p90 DZ - - - p.N1296K 33 Cast F >p75 DZ, OT 1 (95%) DZ, OT c.3291 3292delGC - 34 Val F >p90 DZ, NF - (EXITUS) p.P551R - a P = patient.
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ABCC8 p.Arg598* 16429405:137:1029
status: NEW147 Genetic variants found in ABCC8 gene from HI Spanish cohort Mutations considered pathogenic nt change a aa change a Type E/Ic Domaind Patient Refe PSIC f Polypheng C h c.220C>T p.R74W MIS E2 CL1 P30 NR 2.257 PrD Highly c.331G>C p.G111R MIS E3 TM3 P9 [1] 1.672 PsD Moderately c.563A>G p.N188S MIS E4 TM5 P25 [2] 1.494 Benign Highly c.698T>G p.M233R MIS E5 CL3 P8 NR 2.428 PrD Highly c.584_585insA p.Y195X FS E5 ─ P3, P4 NR ─ ─ ─ c.742C>T p.R248X NON E5 ─ P1a, P1b [3] ─ ─ ─ c.928G>A p.D310N MIS E6 CL3 P12 NR 1.614 PsD Highly c.1347_1348delGA p.V449VfsX493 FS E9 ─ P5 NR ─ ─ ─ c.1332+4438_1631-9207del p.I445FfsX447 FS ─ ─ P19 NR ─ ─ ─ c.1652C>G p.P551R MIS E11 TM10 P34 NR 2.1 PsD Highly c.1732_1746dup p.A578_L582dup IFins E12 ─ P18, P23 NR ─ ─ ─ c.1792C>T p.R598X NON E12 ─ P27 NR ─ ─ ─ c.2156 A>C p.K719T MIS E16 CL6 P31 NR 1.927 PsD Highly c.2142delG p.Q714QfsX724 FS E16 ─ P20 NR ─ ─ ─ c.2394-2A>G ─ AS I19 ─ P21 NR ─ ─ ─ c.2800C>T p.R934X NON E23 ─ P14 NR ─ ─ ─ c.3133_3152del p.L1045LfsX1107 FS E25 ─ P17 [6] ─ ─ ─ c.3291_3292delGC p.L1097LfsX1113 FS E26 ─ P33 NR c.3391A>C p.T1131P MIS E27 CL7 P20 NR 1.777 PsD Moderately c.3443T>G p.L1148R MIS E28 TM14 P28 NR 1.722 PsD Highly c.3576delG p.L1191LfsX1207 FS E29 ─ P1a, P1b, NR ─ ─ ─ c.3751C>T p.R1251X NON E30 ─ P28 NR ─ ─ ─ c.3888C>G p.N1296K MIS E32 TM17 P32 NR 1.924 PsD Highly c.3992-9G>A ─ AS I 32 ─ P14 [4] ─ ─ ─ c.4123-19C>T ─ AS I33 ─ P25 [5] ─ ─ ─ c.4310G>A ─ AS E35 ─ P23 [4] ─ ─ ─ c.4352T>C p.L1451P MIS E36 CL9 P27 NR 1.797 PsD Highly c.4612-2 A>T ─ AS I38 ─ P12 NR ─ ─ ─ c.4619_4620insT p.H1540AfsX1559 FS E39 ─ P17 NR ─ ─ ─ Polimorphisms and unclassified variants nt change a aa change a Type E/Ic SNPid Patientsi Controls NCBI j Exclusion c. 207T>C p.P69P SYN E2 rs1048099 28/46 ─ 0.50 S c. 330C>T p.A110A SYN E3 rs8192695 2/48 ─ 0.04 S c.
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ABCC8 p.Arg598* 16429405:147:907
status: NEW[hide] Preoperative evaluation of infants with focal or d... J Clin Endocrinol Metab. 2004 Jan;89(1):288-96. Stanley CA, Thornton PS, Ganguly A, MacMullen C, Underwood P, Bhatia P, Steinkrauss L, Wanner L, Kaye R, Ruchelli E, Suchi M, Adzick NS
Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation.
J Clin Endocrinol Metab. 2004 Jan;89(1):288-96., [PMID:14715863]
Abstract [show]
Infants with congenital hyperinsulinism often require pancreatectomy. Recessive mutations of the ATP-dependent plasma membrane potassium channel (K(ATP)) genes, SUR1 and K(ir)6.2, cause diffuse hyperinsulinism. K(ATP) channel mutations can also cause focal disease through loss of heterozygosity for maternal 11p, resulting in expression of a paternal mutation. This study evaluated whether focal vs. diffuse hyperinsulinism could be diagnosed by acute insulin response (AIR) tests and whether arterial calcium stimulation/venous sampling (ASVS) could localize focal lesions. Fifty infants with diazoxide-unresponsive hyperinsulinism were studied. Focal lesions occurred in 70% of the cases. Positive AIR calcium occurred in 17 of 30 focal and 10 of 13 diffuse cases (P < 0.04). Positive AIR tolbutamide occurred in 27 of 30 focal vs. seven of 13 diffuse cases (P < 0.02); K(ATP) channel mutations were identified in four of the latter. ASVS localized the lesion in 24 of 33 focal cases (73%) but correctly diagnosed diffuse disease in only four of 13 cases. These results indicate that preoperative AIR tests do not distinguish focal vs. diffuse disease because some K(ATP) channel mutations retain responsiveness to tolbutamide. The ASVS test can be used to localize focal lesions in infants. The combination of ASVS, careful intraoperative histologic analysis, and surgical expertise succeeded in correcting hypoglycemia in 86% of the infants with focal hyperinsulinism.
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205 of alleles SUR1 region Exon 1 F27Sa 1 Exon 2 R74W 2 Exon 4 536-9 del atgga 1 Exon 4 N188S 1 Exon 5 ins 6a.a. 1 Exon 10 R495Qa 1 Exon 10 E501Ka 1 Intron 10 g 1630ϩ1 aa,b 1 Exon 12 R598X 1 Exon 13 1874 del c 1 Exon 15 F686Sa 1 Exon 16 C717X 1 Intron 24 c 2924-9 aa 1 Exon 24 2835-8 del agaga 2 Exon 24 Q954X 1 Exon 25 R999X 2 Exon 29 3576 del g 1 Exon 29 R1215Q 2 Exon 29 R1215Wa,b 2 Intron 32 g 3992-9 a 4 Exon 33 L1350Qa 1 Exon 33 G1401Ra 1 Exon 34 S1387F 1 Exon 34 delF1388 1 Exon 36 D1472Ha 1 Exon 36 D1472Na 1 Kir6.2 region A102Na 1 G134A 1 R136La 1 P266L 1 R301Ha 1 a Novel mutations.
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ABCC8 p.Arg598* 14715863:205:185
status: NEW