ABCMdb

ABCC8 p.Gly111Arg

Predicted by SNAP2:	A: N (57%), C: N (53%), D: D (66%), E: D (71%), F: N (61%), H: D (63%), I: N (87%), K: D (66%), L: N (61%), M: D (53%), N: D (66%), P: D (80%), Q: D (80%), R: D (59%), S: N (66%), T: N (66%), V: N (82%), W: D (75%), Y: D (63%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] [18F-fluoro-L-DOPA PET-CT imaging combined with ge... An Pediatr (Barc). 2008 May;68(5):481-5. Arbizu Lostao J, Fernandez-Marmiesse A, Garrastachu Zumarran P, Martino Casado E, Azcona San Julian C, Carracedo A, Richter Echevarria JA
[18F-fluoro-L-DOPA PET-CT imaging combined with genetic analysis for optimal classification and treatment in a child with severe congenital hyperinsulinism].
An Pediatr (Barc). 2008 May;68(5):481-5., [PMID:18447993]

Abstract [show]
BACKGROUND: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy. The differential diagnosis between focal and diffuse forms of CHI is of great importance when planning surgery. The aim of this article is to show the first case of focal CHI diagnosed in Spain using PET-CT imaging combined with genetic analysis. METHODS: A 13 month child with CHI and normal conventional radiological investigations treated with diazoxide, diet control and feeding by gastrostomy is presented. Genetic analysis of ABCC8 and KCNJ11 genes and PET-TAC using 18F-fluoro-L-DOPA were performed. RESULTS: A pathological mutation (G111R) in the paternal allele of ABCC8 was detected. PET-CT scanning using 18F-fluoro-L-DOPA showed a focus of high uptake in the body of the pancreas compatible with adenoma that was hystopathologically confirmed. After surgical resection the patient is asymptomatic without needing either pharmacological treatment or dietetic control. CONCLUSIONS: The combination of genetic analysis and 18F-fluoro-L-DOPA PET-TAC shows a great potential for the identification, location and guideline for surgery in CHI.

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13 Resultados Se detectó una mutación patogénica (G111R) en el alelo paterno de ABCC8. Login to comment
26 Results A pathological mutation (G111R) in the paternal allele of ABCC8 was detected. Login to comment
70 11 ORIGINALES (481-5) 23/4/08 18:05 Página 482 RESULTADOS Análisis genético El análisis de los genes ABCC8 y KCNJ11 reveló la presencia de la mutación 331G > C en heterocigosis en el exón 3 del gen ABCC8, que origina el cambio de amino- ácido G111R. Login to comment
83 El análisis genético del paciente presentado aquí detectó una única mutación G111R en el alelo paterno de ABCC8, la cual ya había sido descrita previamente en nuestra población8 y su patogenicidad previamente demostrada12. Login to comment

[hide] Molecular and clinical analysis of Japanese patien... J Clin Endocrinol Metab. 2011 Jan;96(1):E141-5. Epub 2010 Oct 13. Yorifuji T, Kawakita R, Nagai S, Sugimine A, Doi H, Nomura A, Masue M, Nishibori H, Yoshizawa A, Okamoto S, Doi R, Uemoto S, Nagasaka H
Molecular and clinical analysis of Japanese patients with persistent congenital hyperinsulinism: predominance of paternally inherited monoallelic mutations in the KATP channel genes.
J Clin Endocrinol Metab. 2011 Jan;96(1):E141-5. Epub 2010 Oct 13., [PMID:20943781]

Abstract [show]
BACKGROUND: Preoperative identification of the focal form of congenital hyperinsulinism is important for avoiding unnecessary subtotal pancreatectomy. However, neither the incidence nor the histological spectrum of the disease is known for Japanese patients. AIMS: The aim of the study was to elucidate the molecular and histological spectrum of congenital hyperinsulinism in Japan. SUBJECTS: Thirty-six Japanese infants with persistent congenital hyperinsulinism were included in the study. METHODS: All exons of the ATP-sensitive potassium channel (K(ATP) channel) genes (KCNJ11 and ABCC8), the GCK gene, and exons 6 and 7 and 10-12 of the GLUD1 gene were amplified from genomic DNA and directly sequenced. In patients with K(ATP) channel mutations, the parental origin of each mutation was determined, and the results were compared with the histological findings of surgically treated patients. In one of the patients with scattered lesions, islets were sampled by laser capture microdissection for mutational analysis. RESULTS: Mutations were identified in 24 patients (66.7%): five in GLUD1 and 19 in the K(ATP) channel genes. Sixteen had a paternally derived, monoallelic K(ATP) channel mutation predictive of the focal form. In 10 patients who underwent pancreatectomy, the molecular diagnosis correctly predicted the histology, more accurately than [18F]-3,4-dihydroxyphenylalanine positron emission tomography scans. Three patients showed focal lesions that occupied larger areas of the pancreas. Preferential loss of the maternal allele was observed in these islets. CONCLUSION: The majority of the Japanese patients with K(ATP) channel hyperinsulinism (84.2%) demonstrated paternally inherited monoallelic mutations that accurately predicted the presence of the focal form.

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76 Parental origin 1 F 9 months 38 ͓2.1͔ 4.8 ͓33͔ 83 ͓49͔ GLUD1 c.661CϾT p.R221C yes ND F, D 2 M 7 months 30 ͓1.7͔ 3 ͓21͔ 132 ͓77͔ GLUD1 c.797AϾG p.Y266C yes ND F, D 3 F 3 months 29 ͓1.6͔ 4 ͓28͔ 246 ͓144͔ GLUD1 c.1336GϾA p.G446S Yes ND F, D 4 M 10 months Ͻ45 ͓2.5͔ 7.7 ͓53͔ 154 ͓90͔ GLUD1 c.1229AϾG p.N410S No ND F, D 5 M 0 d 10 ͓0.6͔ 10 ͓69͔ 250 ͓147͔ GLUD1 c.1229AϾC p.N410T Yes ND F, D 6a F 2 d 31 ͓1.7͔ 30.2 ͓210͔ 78 ͓46͔ ABCC8 c.382GϾA c.3748CϾT p.E128K p.R1250X Yes, Yes Biparental 7 M 2 d 5 ͓0.3͔ 7.5 ͓52͔ 131 ͓77͔ ABCC8 c.2506CϾT c.4575_4587del13 p.R836X p.M1524Mfs1539X Yes, No Biparental F, O 8 M 0 d Ͻ45 ͓2.5͔ 11 ͓76͔ 58 ͓34͔ ABCC8 c.4516GϾA p.E1506K Yes Mat F, D 9a F 1 month Ͻ20 ͓1.1͔ 42.4 ͓294͔ NA ABCC8 c.2506CϾT p.R836X Yes Pat 10a M 2 d 10 ͓0.56͔ 23.5 ͓163͔ NA ABCC8 c.4412-13GϾA - Yes Pat 11a F 0 d 33 ͓1.8͔ 46.6 ͓324͔ 79 ͓46͔ ABCC8 c.3745GϾT p.V1249F No Pat 12a F 3 months 20 ͓1.1͔ 5.16 ͓36͔ 78 ͓46͔ ABCC8 c.2992CϾT p.R998X Yes Pat 13a F 0 d 23 ͓1.3͔ 101 ͓701͔ 45 ͓24͔ ABCC8 c.4608 ϩ 1GϾA - No Pat 14a M 0 d 22 ͓1.2͔ 22.7 ͓158͔ 75 ͓44͔ ABCC8 c.2992CϾT p.R998X Yes Pat 15a M 5 months 33 ͓1.8͔ 5.42 ͓38͔ NA ABCC8 c.2992CϾT p.R998X Yes Pat 16a M 0 d 28 ͓1.6͔ 38.7 ͓269͔ 66 ͓39͔ ABCC8 c.331GϾA p.G111R Yes Pat 17 F 2 months 15 ͓0.8͔ 9.9 ͓69͔ 90 ͓53͔ ABCC8 c.61_62insG p.V21Gfs88X No Pat F, O 18 M 0 d 19.6 ͓1.1͔ 44 ͓306͔ 79 ͓46͔ ABCC8 c.2506CϾT p.R836X Yes Pat F, O 19 F 7 months 35 ͓1.9͔ 11.2 ͓78͔ 97 ͓57͔ ABCC8 c.2506CϾT p.R836X Yes Pat F, O 20 M 4 months Ͻ45 ͓2.5͔ 7.5 ͓52͔ 84 ͓49͔ ABCC8 c.3928_3929insG p.A1310Gfs1405X No Pat F, O 21 M 2 d 38 ͓2.1͔ 3.4 ͓24͔ 91 ͓53͔ ABCC8 c.4186GϾT p.D1396Y No Pat F 22 F 0 d 9 ͓0.5͔ 22 ͓153͔ NA ABCC8 c.2506CϾT p.R836X Yes Pat F, O 23 M 2 d 0 ͓0͔ 17.3 ͓120͔ 317 ͓186͔ ABCC8 c.4412-13GϾA - Yes Pat F, D 24a M 0 d 33 ͓1.8͔ 21.9 ͓152͔ 75 ͓44͔ KCNJ11 c.637GϾA p.A213T No Pat The clinical data are those at the initial presentation. Login to comment

[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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106 Mutations c.220C>T (p.R74W), c.331G>C (p.G111R), and c.563A>G (p.N188S) are situated in the TMD0 domain of SUR1 which is implicated in the strong association between SUR1 and Kir6.2 and modulate trafficking and gating of the channel (Chan et al. 2003). Login to comment
108 It was recently demonstrated that the second substitution G111R constitutes a pathological change (Tornovsky et al 2004). Login to comment
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. Login to comment
147 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. Login to comment
166 ESEfinder score change of some variants of ABCC8 gene nt change aa change ESE changes a SF2-ASF SC35 SRp40 SRp55 Mutations c.220C>T R74W Lost 2.9 Gain 0.64 Gain 1.49 Lost 1.55 c.331G>C G111R M 2.58 - - - c.563A>G N188S - M 0.36 - Gain 0.61 c.2156 A>C K719T - - - Gain 2.14 c.3391A>C T1131P Lost 1.74 c.3443T>G L1148R M +2.12 Gain 2.39 c.3888C>G N1296K ─ ─ Lost 1.73 ─ c.4352T>C L1451P M -0.42 Lost 0.65 Gain 1.54 ─ Polymorphisms and unclassified variants c. 207T>C P69P Gain 1.458 M -0.645 ─ ─ c. 330C>T A110A M -2.524 ─ ─ ─ c. 1686C>T H562H ─ Lost-0.645 M -0.356 M +1.551 c. 1707C>T* A569A Lost 2.397 ─ ─ ─ c. 1947G>A K649K ─ ─ Lost 0.846 M -0.609 c. 2280C>T T760T Lost 2.524 ─ M +0.356 ─ c. 3822G>A R1274R M -2.824 Lost 2.382 ─ c. 4108T>G S1370A ─ M +0.648 ─ ─ c. 4717G>A V1573I ─ ─ M -0.609 a Lost (or gain) of an ESE below (above) the threshold values (SF2-ASF = 1.956; SC35 = 2.383; SRp40 = 2.67; SRp55 =2.676; Cartegni et al. 2003) are indicated. Login to comment

[hide] Hyperinsulinism of infancy: novel ABCC8 and KCNJ11... J Clin Endocrinol Metab. 2004 Dec;89(12):6224-34. Tornovsky S, Crane A, Cosgrove KE, Hussain K, Lavie J, Heyman M, Nesher Y, Kuchinski N, Ben-Shushan E, Shatz O, Nahari E, Potikha T, Zangen D, Tenenbaum-Rakover Y, de Vries L, Argente J, Gracia R, Landau H, Eliakim A, Lindley K, Dunne MJ, Aguilar-Bryan L, Glaser B
Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.
J Clin Endocrinol Metab. 2004 Dec;89(12):6224-34., [PMID:15579781]

Abstract [show]
Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K(IR)6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on beta-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.

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101 ABCC8 -64 c3g Promoter gcc gcc ccc Promoter 11 gGc G70E 2 ccc ggg cac Missense 5 gAg G111R 3 gcc ggg atg Missense 3 Agg 2154 ϩ 3a3g Intron 15 agg tat ggc Splice-site 6, 10 tGt R836X 21 cag cga atc Nonsense 2 Tga 1113 ins T 27 ttt ttt gag Single-base insertion 7 ttt ttt Tga 3992-9 g3a Intron 32 cgc aag cgt Splice-site 1 aaA G1342E 33 caa ggg aag Missense 6 gAg R1419H 35 ctg cgc tca Missense 5 cAc R1494W 37 gcc cgg gcc Missense 4 Tgg KCBJ11 ϩ88 g3t Promoter gaa gtg agg Promoter 9 Ttg P254L Exon 1 gcc cCg ctg Missense 8 cTg a For each mutation, the upper line indicates the wt sequence, and the lower line indicates the mutant sequence. Login to comment
164 When the mutations in ABCC8 (G70E, G111R, R836X, G1343E, R1419H, and R1494W) were expressed alone, all except R836X were photolabeled with the high-affinity sulfonylurea ligand [125 I]- azido-glibenclamide (data not shown). Login to comment
180 In contrast, the mature form, which is indicative of channels trafficking at least to the Golgi, was present only in the G70E homozygote, in the G70E/R1419H compound heterozygote, and to a lesser extent, in G111R. Login to comment
185 The first three SUR1 mutant channels, G70E homozygote, G70E/ R1419H compound heterozygote, and G111R, were expressed at the plasma membrane, albeit at much lower levels than the wild-type channel. Login to comment
188 We confirmed that channel activity of the G70E and G111R mutants was decreased when compared with wild-type controls. Login to comment
236 COS cells coexpress wild-type (wt) KIR6.2 with SUR1 mutations (G70E, G70E/R1419H, G111R, G1343E, R1419H, and R1494W) or coexpress wt SUR1 with KIR6.2 mutation (P254L). Login to comment
242 Homozygous expression of G70E and G111R had reduced surface expression, whereas mutations R836X, G1343E, R1419H, R1494W, and P254L did not reach the plasma membrane at all, although they did associate with their respective wt partner as shown in Fig. 5A (lower panel). Login to comment
250 Only G70E (8 ␮g), G111R (8 ␮g), and compound heterozygote G70E/R1419H (4 ␮g/4 ␮g) reconstituted with wt KIR6.2 (1 ␮g) show reduced efflux. Login to comment
280 In the current study, we describe two different missense mutations in the same domain, G70E and G111R. Login to comment

[hide] Clinical and molecular characterisation of 300 pat... Eur J Endocrinol. 2013 Mar 15;168(4):557-64. doi: 10.1530/EJE-12-0673. Print 2013 Apr. Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K
Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism.
Eur J Endocrinol. 2013 Mar 15;168(4):557-64. doi: 10.1530/EJE-12-0673. Print 2013 Apr., [PMID:23345197]

Abstract [show]
BACKGROUND: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI. AIM: To characterise the clinical and molecular aspects of a large cohort of patients with CHI. METHODOLOGY: Three hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A). RESULTS: Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3). CONCLUSIONS: A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.

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77 The most common mutations were the splice site mutation c.3992-9GOA and the missense mutation p.G111R, found in six patients each. Login to comment
167 This series identified a missense mutation p.G111R in six unrelated patients with severe, diazoxide-unresponsive disease, of Indian background. Login to comment
169 The recognition of the p.G111R mutation exclusively in patients from an Indian ethnic background suggests a founder effect. Login to comment

[hide] Clinical and histological heterogeneity of congeni... Eur J Endocrinol. 2014 Dec;171(6):685-95. doi: 10.1530/EJE-14-0353. Epub 2014 Sep 8. Arya VB, Guemes M, Nessa A, Alam S, Shah P, Gilbert C, Senniappan S, Flanagan SE, Ellard S, Hussain K
Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations.
Eur J Endocrinol. 2014 Dec;171(6):685-95. doi: 10.1530/EJE-14-0353. Epub 2014 Sep 8., [PMID:25201519]

Abstract [show]
CONTEXT: Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported. OBJECTIVE: The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. DESIGN: A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted. RESULTS: Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 l-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography 18F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (n=8) or 18F DOPA-PET CT (n=27). Diffuse, indeterminate and focal disease was identified in 13, 1 and 21 patients respectively. Two patients with suspected diffuse disease were identified to have focal disease on histology. CONCLUSIONS: Paternally inherited heterozygous ABCC8/KCNJ11 mutations can manifest as a wide spectrum of CHI with variable 18F DOPA-PET CT/histological findings and clinical outcomes. Focal disease was histologically confirmed in 24/53 (45%) of CHI patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations.

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70 (c.1629-2A>C) Walker B *R177W *M209I *I284del E292K T294M G312C COOH COOH NH2 M1 M2 6 1 TMD0 TMD1 TMD2 2 3 4 5 7 8 9 10 11 12 13 14 15 16 17 p.*391Rext*94 *T62M R1494W Q954X G111R A113V *V601I *A1153T D1031N L1171X A1263T V185fs Intracellular NH2 NBD2 NBD1 Cell membrane Figure 1 Paternal mutations mapped onto the SUR1 and Kir6.2 protein. Login to comment
74 Patient ID GA (weeks), birth weight (g) Gender Age at presentation (weeks) Blood glucose (mmol/l) Serum insulin (mU/l) Mutation protein description (DNA description) LOH Dzx Resp PET CT/PVS Outcome ABCC8 1 40, 3150 Male 52 2.4 4.3 L1431F/N (c.4291COT/N) Yes - On Dzx at 6.4 years 2 40, 4000 Male 2 2.4 1.9 p.?/N (c.2697C4AOT/N) Yes - Off Dzx at 2 years 3 40, 5010 Female !1 2.6 8.6 E1507K/N (c.4519GOA/N) Yes - On Dzx at 2.3 years 4 40, 5600 Male !1 2.0 7.5 A1508P/N (c.4522GOC/N) Yes - On Dzx at 12 years 5 37, 4820 Male !1 2.0 9.0 A1153T/N (c.3457GOA/N) Yes - On Dzx at 4 years 6 38, 3630 Female 72 3.1 !2 A1153T/N (c.3457GOA/N) Yes - On Dzx at 2 years 8 35, 2820 Male !1 1.2 12.9 A1185V/N (c.3554COT/N) Yes - Off Dzx at 8 months 9 36, 4450 Male !1 2 28.5 p.?/N (c.3992-9GOA/N) Yes - Off Dzx after 4.5 months 10 41, 2780 Female !1 1 9.3 D1472N/N (c.4414GOA/N) Yes - Off Dzx after 10 months 11 38, 3750 Male !1 2.6 5.90 V601I/N (c.1801GOA/N) Yes - Off Dzx after 14 months 13 40, 4160 Female !1 2.4 14.8 V185fs/N (c.554delT/N) No Diffuse Off octreotide at 5 years 14 37, 3090 Male !1 0.6 12.4 p.?/N (c.3992-9GOA/N) No Focal On octreotide at 9.5 years 15 40, 3600 Male !1 2.7 6.7 H627fs/N (c.1879delC/N) No Diffuse Off octreotide at 18 months 16 40, 4700 Female !1 2.0 !2 E1507K/N (c.4519GOA/N) NA - No treatment required 17 40, 4200 Male !1 1.0 !2 D1031N/N (c.3091GOA/N) NA - No treatment required 18 41, 4850 Male !1 1.2 10.1 M1V/N (c.1AOG/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 19 38, 2400 Male !1 2.1 16.3 D1194V; R1437Q/N (c.3581AOT; c.4310GOA/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 20 40, 4580 Female !1 1.1 103 A1493T/N (c.4477GOA/N) Yes a No Diffuse Near-total pancreatectomy (95%) 21 40, 4600 Male !1 1.2 22.5 K890fs/N (c.2669_2675del/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 22 40, 4335 Male !1 2.6 3.4 p.?/N (c.3992-9GOA/N) Yes No Focal Partial pancreatectomy 23 40, 3030 Male !1 1.8 15.6 p.?/N (c.3992-9GOA/N) Yes No Focal Partial pancreatectomy 24 40, 2770 Male !1 2.2 3.4 p.?/N (c.580-1GOC/N) No Indeterminate (PVS) Partial pancreatectomy - focal lesion on histology 25 41, 4290 Male 2 2.3 4.32 E128K/N (c.382GOA/N) No Focal Hypoglycaemia resolved after removal of focal lesion 27 40, 5095 Male !1 2.0 10.5 L1171X/N (c.3512delT/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 29 37, 3560 Male !1 1.6 21.8 p.?/N (c.1629-2AOC/N) No Focal Hypoglycaemia resolved after removal of focal lesion 30 40, 2750 Male !1 1.5 16.4 G111R/N (c.331GOA/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 31 37, 3340 Male !1 2.1 15 H627fs/N (c.1879delC/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 32 41, 4950 Male !1 1.2 11.95 R934X/N (c.2800COT/N) No Focal Hypoglycaemia resolved after removal of focal lesion 33 40, 3080 Female 12 1.5 4.6 S12X/N (c.35COA/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 34 39, 3600 Male !1 2.5 8 R1494W/N (c.4480COT/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 37 36, 3410 Male !1 0.9 17.42 R1494W/N (c.4480COT/N) No Focal Partial pancreatectomy Table 1 Continued Patient ID GA (weeks), birth weight (g) Gender Age at presentation (weeks) Blood glucose (mmol/l) Serum insulin (mU/l) Mutation protein description (DNA description) LOH Dzx Resp PET CT/PVS Outcome 38 39, 4900 Female !1 1.4 23.61 A113V/N (c.338COT/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 39 36, 3210 Male !1 0.6 114 Mosaic Q54X (c.160COT) No Diffuse Near-total pancreatectomy (95%) 40 41, 4300 Female !1 2.1 17 Q954X/N (c.2860COT/N) No Diffuse Near-total pancreatectomy (95%) 41 36, 2730 Male !1 ? Login to comment