ABCC8 p.Asn188Ser
| Predicted by SNAP2: | A: N (72%), C: N (82%), D: N (57%), E: N (53%), F: N (82%), G: N (72%), H: N (72%), I: N (72%), K: N (57%), L: N (78%), M: N (61%), P: D (59%), Q: N (61%), R: N (61%), S: N (82%), T: N (87%), V: N (78%), W: D (59%), Y: N (93%), |
| Predicted by PROVEAN: | A: D, C: D, D: N, E: D, F: D, G: D, H: N, I: D, K: D, L: D, M: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] Insight in eukaryotic ABC transporter function by ... FEBS Lett. 2006 Feb 13;580(4):1064-84. Epub 2006 Jan 19. Frelet A, Klein M
Insight in eukaryotic ABC transporter function by mutation analysis.
FEBS Lett. 2006 Feb 13;580(4):1064-84. Epub 2006 Jan 19., 2006-02-13 [PMID:16442101]
Abstract [show]
With regard to structure-function relations of ATP-binding cassette (ABC) transporters several intriguing questions are in the spotlight of active research: Why do functional ABC transporters possess two ATP binding and hydrolysis domains together with two ABC signatures and to what extent are the individual nucleotide-binding domains independent or interacting? Where is the substrate-binding site and how is ATP hydrolysis functionally coupled to the transport process itself? Although much progress has been made in the elucidation of the three-dimensional structures of ABC transporters in the last years by several crystallographic studies including novel models for the nucleotide hydrolysis and translocation catalysis, site-directed mutagenesis as well as the identification of natural mutations is still a major tool to evaluate effects of individual amino acids on the overall function of ABC transporters. Apart from alterations in characteristic sequence such as Walker A, Walker B and the ABC signature other parts of ABC proteins were subject to detailed mutagenesis studies including the substrate-binding site or the regulatory domain of CFTR. In this review, we will give a detailed overview of the mutation analysis reported for selected ABC transporters of the ABCB and ABCC subfamilies, namely HsCFTR/ABCC7, HsSUR/ABCC8,9, HsMRP1/ABCC1, HsMRP2/ABCC2, ScYCF1 and P-glycoprotein (Pgp)/MDR1/ABCB1 and their effects on the function of each protein.
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No. Sentence Comment
426 Shyng et al. [204] have reported that H125Q, N188S, F591L, T1139M, R1215Q and G1382S generated functional channels in the absence of ATP, indicating that the lack or reduction of KATP channel sensitivity to MgADP is a common molecular defect associated with the disease.
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ABCC8 p.Asn188Ser 16442101:426:45
status: NEW[hide] Complex ABCC8 DNA variations in congenital hyperin... Clin Endocrinol (Oxf). 2007 Jul;67(1):115-24. Epub 2007 Apr 27. Muzyamba M, Farzaneh T, Behe P, Thomas A, Christesen HB, Brusgaard K, Hussain K, Tinker A
Complex ABCC8 DNA variations in congenital hyperinsulinism: lessons from functional studies.
Clin Endocrinol (Oxf). 2007 Jul;67(1):115-24. Epub 2007 Apr 27., [PMID:17466004]
Abstract [show]
OBJECTIVE: Congenital hyperinsulinism (CHI) is a cause of persistent and severe hypoglycaemia in infancy. Mutations in the genes ABCC8 and KCNJ11 encoding SUR1 and Kir6.2, respectively, are the commonest cause of CHI. We investigated whether the possession of two DNA variants leading to coding changes in a single allele of ABCC8 can affect the potential mechanism of disease pathogenesis. DESIGN AND PATIENTS: We studied two patients with complex mutations in the ABCC8 gene with CHI and used in vitro studies to explore the potential disease mechanism and the contribution of the various mutant allelles. RESULTS: The first case had diffuse disease and was homozygous for the mutations D1193V and R1436Q in SUR1. Channel complexes containing the D1193V mutant were delivered to the plasma membrane and were functional and those containing R1436Q were also present at the plasma membrane but were nonfunctional. Combining the two mutations (SUR1D1193V/R1436Q) led to intracellular retention of the channel complex. In a second family, the patient had histologically focal disease and was heterozygous for two mutations from his father (G228D and D1471N) and one from his mother (V1572I). SUR1 G228D and D1471N singly or in combination led to intracellular retention of the channel complex and loss of function. By contrast, V1572I is trafficked appropriately and is functional, consistent with a mechanism of reduction to hemizygosity of paternal ABCC8 in focal disease. V1572I is likely to be a benign DNA variant. CONCLUSION: In one patient the combination of two coding variants led to intracellular retention of channel complex. In a second patient, functional studies allowed us to unravel the DNA variants likely to be causing the abrogation of ATP-sensitive K(+) channel function.
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23 Whereas compound mutations occur in approximately 13% of CHI patients,39 the simultaneous presence of two homozygous CHI mutations has to our knowledge only been reported in one patient, in which one of the mutations (N188S) was thought to be nonfunctional.40 In this report,we describe two patients with more than one suspected mutation in diffuse and focal disease and delineate the consequences these DNA variations have on KATP channel function.
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ABCC8 p.Asn188Ser 17466004:23:218
status: NEW[hide] Functional analyses of novel mutations in the sulf... Diabetes. 1998 Jul;47(7):1145-51. Shyng SL, Ferrigni T, Shepard JB, Nestorowicz A, Glaser B, Permutt MA, Nichols CG
Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy.
Diabetes. 1998 Jul;47(7):1145-51., [PMID:9648840]
Abstract [show]
The ATP-sensitive potassium channel, K(ATP) channel, a functional complex of the sulfonylurea receptor 1, SUR1, and an inward rectifier potassium channel subunit, Kir6.2, regulates insulin secretion in the pancreas. Mutations in both the Kir6.2 and SUR1 genes are associated with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), a disorder of pancreatic beta-cell function characterized by excess insulin secretion and hypoglycemia. We have studied the functional properties of novel SUR1 mutations identified in PHHI patients, including H125Q, N188S, F591L, T1139M, R1215Q, G1382S, and R1394H. R1394H and deltaF1388 SUR1, a previously identified PHHI mutation, resulted in no functional channels when coexpressed with Kir6.2 in COS cells, while H125Q, N188S, F591L, T1139M, R1215Q, and G1382S SUR1 generated functional channels in the absence of ATP. With the exception of N188S and H125Q, all mutants had reduced response to stimulation by MgADP. These results indicate that lack of, or reduction of, K(ATP) channel sensitivity to MgADP is a common molecular defect associated with the disease. The mutant channels also showed varied response to activation by the potassium channel opener diazoxide. Because these mutations are distributed throughout the molecule, our data have new implications for structure-function relationships of the K(ATP) channel, suggesting that structural elements in SUR1 outside of the two nucleotide-binding folds are also important in regulating channel activity.
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2 We have studied the functional properties of novel SUR1 mutations identified in PHHI patients, including H125Q, N188S, F591L, T1139M, R1215Q, G1382S, and R1394H.
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ABCC8 p.Asn188Ser 9648840:2:112
status: NEW3 R1394H and F1388 SUR1, a previously identified PHHI mutation, resulted in no functional channels when coexpressed with Kir6.2 in COS cells, while H125Q, N188S, F591L, T1139M, R1215Q, and G1382S SUR1 generated functional channels in the absence of ATP.
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ABCC8 p.Asn188Ser 9648840:3:153
status: NEW4 With the exception of N188S and H125Q, all mutants had reduced response to stimulation by MgADP.
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ABCC8 p.Asn188Ser 9648840:4:22
status: NEW75 The positions of the seven newly identified SUR1 mutations that are associated with the disease PHHI are shown in Fig. 1, including H125Q, N188S, F591L, T1139M, R1215Q, G1382S, and R1394H on both SUR1 topology models.
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ABCC8 p.Asn188Ser 9648840:75:139
status: NEW112 Compared with wild-type channels, H125Q had a slightlygreater response to diazoxide (P < 0.1, ANOVA), N188S hada response that is similar to the wild-type channel (NS, ANOVA), T1139M and G1382S mutant channels had slightly reduced responses, while F591L and R1215Q channels had severely reduced responses (P < 0.005 and 0.025, respectively, ANOVA) (Fig. 6).
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ABCC8 p.Asn188Ser 9648840:112:102
status: NEW138 One patient was homozygous for the N188S mutation and another compound heterozygousforthis mutation and a novel splice-site mutation 3992-3 c-to-g (M.A.P., B.G., unpublished observations).
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ABCC8 p.Asn188Ser 9648840:138:35
status: NEW156 With the exception of N188S and H125Q, which formed channels that were indistinguishable from the wild-type in terms of regulation of the channel by nucleotides and diazoxide, all other mutants caused defects of various severity in the resulting channels.
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ABCC8 p.Asn188Ser 9648840:156:22
status: NEW163 This is particularly true of the N188S mutation, which alters channel function only minimally in vitro but is associated with severe clinical disease.
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ABCC8 p.Asn188Ser 9648840:163:33
status: NEW175 Five others (H125Q, N188S, F591L, T1139M, and R1215Q) are outside of the predicted nucleotide-binding folds.
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ABCC8 p.Asn188Ser 9648840:175:20
status: NEW176 However, except for N188S and H125Q, these mutations all show some defects in regulation of the channel by MgADP or by diazoxide.
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ABCC8 p.Asn188Ser 9648840:176:20
status: NEW183 1150 DIABETES, VOL. 47, JULY 1998 SUR1 MUTATIONS AND KATP CHANNELS TABLE 1 Clinical characteristics of the PHHI patients bearing SUR1 mutations Clinical Diazoxide Patient Allele 1 Allele 2 Onset severity responsiveness Treatment G2,4 F1388 F1388 <1 week Severe No Octreotide H2 N188S N188S ??
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ABCC8 p.Asn188Ser 9648840:183:278
status: NEWX
ABCC8 p.Asn188Ser 9648840:183:284
status: NEW185 Pancreatectomy BV N188S 3992-3 c-to-g <1 week Severe No Pancreatectomy CB H125Q F1388 1 year Mild No Pancreatectomy Q R1215Q 3992-9 g-to-a <1 week Severe Inadequate Pancreatectomy AO R1394H 3992-9 g-to-a < week Severe No Pancreatectomy BI F591L - <1 week Mild Yes Diazoxide BU G1382S - <1 week Severe ??
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ABCC8 p.Asn188Ser 9648840:185:18
status: NEW[hide] Genetic heterogeneity in familial hyperinsulinism. Hum Mol Genet. 1998 Jul;7(7):1119-28. Nestorowicz A, Glaser B, Wilson BA, Shyng SL, Nichols CG, Stanley CA, Thornton PS, Permutt MA
Genetic heterogeneity in familial hyperinsulinism.
Hum Mol Genet. 1998 Jul;7(7):1119-28., [PMID:9618169]
Abstract [show]
Familial hyperinsulinism (HI) is a disorder characterized by dysregulation of insulin secretion and profound hypoglycemia. Mutations in both the Kir6.2 and sulfonylurea receptor (SUR1) genes have been associated with the autosomal recessive form of this disorder. In this study, the spectrum and frequency of SUR1 mutations in HI and their significance to clinical manifestations of the disease were investigated by screening 45 HI probands of various ethnic origins for mutations in the SUR1 gene. Single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses of genomic DNA revealed a total of 17 novel and three previously described mutations in SUR1 . The novel mutations comprised one nonsense and 10 missense mutations, two deletions, three mutations in consensus splice-site sequences and an in-frame insertion of six nucleotides. One mutation occurred in the first nucleotide binding domain (NBF-1) of the SUR1 molecule and another eight mutations were located in the second nucleotide binding domain (NBF-2), including two at highly conserved amino acid residues within the Walker A sequence motif. The majority of the remaining mutations was distributed throughout the three putative transmembrane domains of the SUR1 protein. With the exception of the 3993-9G-->A mutation, which was detected on 4.5% (4/88) disease chromosomes, allelic frequencies for the identified mutations varied between 1.1 and 2.3% for HI chromosomes, indicating that each mutation was rare within the patient cohort. The clinical manifestations of HI in those patients homozygous for mutations in the SUR1 gene are described. In contrast with the allelic homogeneity of HI previously described in Ashkenazi Jewish patients, these findings suggest that a large degree of allelic heterogeneity at the SUR1 locus exists in non-Ashkenazi HI patients. These data have important implications for genetic counseling and prenatal diagnosis of HI, and also provide a basis to further elucidate the molecular mechanisms underlying the pathophysiology of this disease.
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63 Mutations within the SUR1 gene Patient Exon or intron Nucleotide changea Codona predicted effect Domainb Restriction site change Frequency (%) HI chromosomes (n = 88) Segregation demonstrated Frequency 200 normal chromosomes A1 exon 2 221G→A R74Q Tm PstI 1 (1.1%) NA 0 B2d exon3 375C→G H125Q Tm DdeIc 1 (1.1%) NA 0 C3e exon 4 563A→G N188S Tm TspRI 1 (1.1%) yes 0 D4 exon 6 949delC 317fs/ter Tm Bsp1286I 1 (1.1%) yes 0 E5 exon 8 1216A→G N406D Tm XcmI 1 (1.1%) NA 0 F6f intron 10 1630+1G→T aberrant splicing Tm BsrI 2 (2.3%) yes 0 G7 exon 12 1773C→G F591L Tm BsoF1 1 (1.1%) no 0 H8 exon 13 1893delT 631fs/ter Tm BstNI 1 (1.1%) yes 0 F6f intron 15 2117-1G→A aberrant splicing NBF-1 PstI 1 (1.1%) yes 0 I9 exon 24 2860C→T Q954X - BstNI 1 (1.1%) yes 0 J10g exon 28 3416C→Th T1139M Tm NlaIII 1 (1.1%) yes 0 K11 exon 29 3644G→A R1215Q Tm NciI 1 (1.1%) yes 0 J10g intron 32 3992-9G→Ai aberrant splicing NBF-2 NciI 4 (4.5%) yes 0 C3e intron 32 3992-3C→G aberrant splicing NBF-2 AvaI 1 (1.1%) yes 0 L12 exon 34 4135G→C G1379R NBF-2 EagI 1 (1.1%) yes 0 M13 exon 34 4144G→A G1382S NBF-2 BglI 1 (1.1%) yes 0 B2d exon 34 4162delTTCi,j delF 1388 NBF-2 BseRI 1 (1.1%) yes 0 J10g exon 34 4181G→Ah R1394H NBF-2 DraIII 1 (1.1%) yes 0 N14 exon 35 4310G→Ai aberrant splicing NBF-2 MspI 1 (1.1%) yes 0 O15 exon 37 4525insCGGCTT insertion of AlaSer ft d 1508 NBF-2 PvuIIk 1 (1.1%) yes 0 after codon 1508 aNucleotide and codon positions are according to the full-length human SUR1 cDNA sequence incorporating the alternative splicedform of exon 17 (GenBank accession nos L78208 and L78216).
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ABCC8 p.Asn188Ser 9618169:63:354
status: NEW200 A model for SUR1 (29) predicts that the remaining seven missense mutations (Arg74Gln, His125Gln, Asn188Ser, Asn406Asp, Phe591Leu, Thr1139Met, Arg1215Gln) are located either within transmembrane segments or are present on the extracellular or cytoplasmic loops connecting adjacent trans- membranehelices.Theidentificationofthesemissensemutations in HI patients provides a basis for further studies to elucidate the functions of these transmembrane domains in SUR1 and KATP channel activity.
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ABCC8 p.Asn188Ser 9618169:200:97
status: NEW[hide] Pancreatic beta-cell stimulation tests in transien... Acta Paediatr. 2001 Oct;90(10):1116-20. Christesen HB, Feilberg-Jorgensen N, Jacobsen BB
Pancreatic beta-cell stimulation tests in transient and persistent congenital hyperinsulinism.
Acta Paediatr. 2001 Oct;90(10):1116-20., [PMID:11697420]
Abstract [show]
In congenital hyperinsulinism (HI). the in vivo pancreatic beta-cell function is poorly described. Among 14 neonates with severe hyperinsulinaemic hypoglycaemia, 2 patients had very prolonged or persistent hypoglycaemia and mutation in the sulphonylurea receptor SURI gene. Patient 1 had transient HI and was treated medically for 3.5 mo before clinical remission was seen. He had initially very high basal and stimulated C-peptide and insulin levels, followed by a state of normal preprandial values, but blunted beta-cell glucose sensitivity, before complete beta-cell normalization occurred. A single. paternal SURI mutation, G1382S, was found suggesting focal type HI. Patient 2 had persistent HI and underwent 3 pancreas resections up to the age of 2 y, 7 mo, followed by a state of mild diabetes. On biopsy, diffuse-type beta-cell hypertrophy was seen. The beta-cell response to glucose and glucagon stimulation was blunted before, as well as after, pancreas resections. Compound heterozygosity for the SUR1 mutations 3992-3c to g and N188S was found. CONCLUSION: Transient, possibly focal, HI with paternal SUR1 mutation was associated with a gradual, but complete normalization of the in vivo beta-cell function; in the diffuse type HI, a blunted beta-cell response to glucose and glucagon stimulation persisted. In vivo beta-cell stimulation tests may contribute to the characterization of the HI subtypes.
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No. Sentence Comment
12 Compound heterozygosity for the SUR1 mutations 3992-3c to g and N188S was found.
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ABCC8 p.Asn188Ser 11697420:12:64
status: NEW111 The maternal exon 5 missense mutation N188S has also been found in a homozygous proband with severe HI (12).
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ABCC8 p.Asn188Ser 11697420:111:38
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.Asn188Ser 15562009:54:264
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.Asn188Ser 15562009:107:131
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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No. Sentence Comment
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).
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ABCC8 p.Asn188Ser 16429405:106:65
status: NEW109 Finally, mutation N188S detected in homozygosis in patient P25 had been previously reported by Nestorowicz et al. (1998) associated with severe clinical disease, although it was reported by Shyng et al. (1998), that this mutation alters channel function only minimally in vitro.
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ABCC8 p.Asn188Ser 16429405:109:18
status: NEW111 This substitution appears as a pathogenic mutation in the Human Gene Mutation Database which seems to support that N188S produces a non pathogenic change.
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ABCC8 p.Asn188Ser 16429405:111:115
status: NEW137 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.Asn188Ser 16429405:137:942
status: NEWX
ABCC8 p.Asn188Ser 16429405:137:965
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.Asn188Ser 16429405:147:286
status: NEW166 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.
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ABCC8 p.Asn188Ser 16429405:166:213
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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No. Sentence Comment
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.Asn188Ser 14715863:205:84
status: NEW[hide] A point mutation inactivating the sulfonylurea rec... Diabetes. 1999 Feb;48(2):408-15. Otonkoski T, Ammala C, Huopio H, Cote GJ, Chapman J, Cosgrove K, Ashfield R, Huang E, Komulainen J, Ashcroft FM, Dunne MJ, Kere J, Thomas PM
A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.
Diabetes. 1999 Feb;48(2):408-15., [PMID:10334322]
Abstract [show]
Mutations in genes encoding the ATP-regulated potassium (K(ATP)) channels of the pancreatic beta-cell (SUR1 and Kir6.2) are the major known cause of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We collected all cases of PHHI diagnosed in Finland between 1983 and 1997 (n = 24). The overall incidence was 1:40,400, but in one area of Central Finland it was as high as 1:3,200. Haplotype analysis using polymorphic markers spanning the SUR1/Kir6.2 gene cluster confirmed linkage to the 11p region. Sequence analysis revealed a novel point mutation in exon 4 of SUR1, predicting a valine to aspartic acid change at amino acid 187 (V187D). Of the total cases, 15 affected individuals harbored this mutation in heterozygous or homozygous form, and all of these had severe hyperinsulinemia that responded poorly to medical treatment and required subtotal pancreatectomy. No K(ATP) channel activity was observed in beta-cells isolated from a homozygous patient or after coexpression of recombinant Kir6.2 and SUR1 carrying the V187D mutation. Thus, the mutation produces a nonfunctional channel and, thereby, continuous insulin secretion. This unique SUR1 mutation explains the majority of PHHI cases in Finland and is strongly associated with a severe form of the disease. These findings provide diagnostic and prognostic utility for suspected PHHI patients.
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No. Sentence Comment
212 Interestingly, one of these mutations (N188S) lies adjacent to that reported here, at the cytosolic end of the predicted fifth transmembrane domain (using the topology of Tsnuandy et al. [28]).
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ABCC8 p.Asn188Ser 10334322:212:39
status: NEW213 The N188S mutation does not alter the sensitivity of the KATP channel to ATP or Mg-ADP, butappears to reduce the level of functional expression (31).
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ABCC8 p.Asn188Ser 10334322:213:4
status: NEW214 The V187D mutation appears to be more severe than N188S, as we could not observe any KATP channel activity in excised patches.
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ABCC8 p.Asn188Ser 10334322:214:50
status: NEW[hide] p57(KIP2) expression in normal islet cells and in ... Diabetes. 2001 Dec;50(12):2763-9. Kassem SA, Ariel I, Thornton PS, Hussain K, Smith V, Lindley KJ, Aynsley-Green A, Glaser B
p57(KIP2) expression in normal islet cells and in hyperinsulinism of infancy.
Diabetes. 2001 Dec;50(12):2763-9., [PMID:11723059]
Abstract [show]
Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea receptor-1 (SUR1) or the inward rectifying K(+) channel Kir6.2, two subunits of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all beta-cells within the pancreas. Focal HI consists of adenomatous hyperplasia within a limited region of the pancreas, and it is caused by somatic loss of heterozygosity (LOH), including maternal Ch11p15-ter in a beta-cell precursor carrying a germ-line mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, some of which, including p57(KIP2) and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57(KIP2) expression in different islet cell types, in control pancreases from different developmental stages (n = 15), and in pancreases from patients with both diffuse (n = 4) and focal HI (n = 9). Using immunofluorescence and computerized image analysis, we quantified IGF-II expression in beta-cells from patients with focal HI (n = 8). Within the pancreas, p57(KIP2) was specifically localized to the endocrine portion. beta-Cells demonstrated the highest frequency of expression (34.9 +/- 2.7%) compared with approximately 1-3% in other cell types. The fraction of beta-cells expressing p57(KIP2) did not vary significantly during development. beta-Cells within the focal lesions did not express p57(KIP2), whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57(KIP2) is expressed and is paternally imprinted in human pancreatic beta-cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57(KIP2) expression in beta-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the beta-cell failure observed in diabetes.
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82 Sex Birth weight (kg) Age of onset (months) Age at surgery (months) Postoperative status Paternal mutation Maternal mutation Diffuse HI 1 F 4.1 1.25 1.5 Hypoglycemic 3992-3 c to g N188S 2 M 3.6 Birth 1.6 Diabetes delcP317 delcP317 3 M 5.04 Birth 3.25 Hypoglycemic Kir Y12X Kir Y12X 4 M 4.4 Birth 13 Hypoglycemic 3992-9 g to a delF1388 Focal HI 5 M 5.36 Birth 0.5 Euglycemic 3992-9 g to a None found 6 M 3.19 Birth 2 Euglycemic R1494Q None found 7 F 3.3 5 6 Euglycemic No DNA - 8 F 3.25 Birth 0.833 Euglycemic None found* None found 9 M 4.18 Birth 1.25 Diabetes None found None found 10 M 3.61 Birth 5.5 Euglycemic None found None found 11 F 3 Birth 12 - No DNA - 12 M 4 Birth 1.5 Diabetes None found None found 13 M 3.9 Birth 2 Euglycemic No DNA - 14 M 3.8 Birth 3 Diabetes No DNA - 15 M 3.63 10 11 Euglycemic A1493T None found Subjects 1-13 were evaluated for p57K1P2 expression, whereas subjects 8-15 were evaluated for IGF-II expression.
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ABCC8 p.Asn188Ser 11723059:82:180
status: NEW[hide] Clinical characteristics and phenotype-genotype an... Eur J Endocrinol. 2014 Jun;170(6):885-92. doi: 10.1530/EJE-14-0045. Epub 2014 Mar 31. Demirbilek H, Arya VB, Ozbek MN, Akinci A, Dogan M, Demirel F, Houghton J, Kaba S, Guzel F, Baran RT, Unal S, Tekkes S, Flanagan SE, Ellard S, Hussain K
Clinical characteristics and phenotype-genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations.
Eur J Endocrinol. 2014 Jun;170(6):885-92. doi: 10.1530/EJE-14-0045. Epub 2014 Mar 31., [PMID:24686051]
Abstract [show]
OBJECTIVE: Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype-phenotype correlations and describe the treatment outcome of Turkish CHI patients. DESIGN AND METHODS: A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected. RESULTS: Diazoxide unresponsiveness was observed in nearly half of the patients (n=17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (n=18), mutations were identified in two patients (11%). Genotype-phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P<0.0001).Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydrate-rich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients. CONCLUSIONS: This is the largest study to report genotype-phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.
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67 The remaining six ABCC8 mutations, p.R168C, p.N188S, p.L533P, p.W232G, p.R842Q and p.F591L were each identified in a single patient.
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ABCC8 p.Asn188Ser 24686051:67:46
status: NEW85 Gene Current age (year) Exon/intron DNA description Protein description Consequence Transmission Treatment Follow-up Developmental delay Comments Diazoxide responsive Octreotide responsive Pancreatectomy (histology) ABCC8 1 3.9 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide CCC Novel mutation 2 0.7 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide Novel mutation 3 9.1 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K K K Irregular CCCC Novel mutation 4 0.7 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide C Novel mutation 5 0.2 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide Novel mutation 6 0.7 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K K C (diffuse) Remission 7 0.7 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K C C (diffuse) Octreotide 8 Died Exon 28 c.3512del p.Leu1171fs Frameshift Heterozygous paternal K K C (diffuse) Died 9 5.8 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K C K Octreotide CCC Ectodermal dysplasia 10 9.6 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K C K Octreotide CCC 11 0.7 Exon 4 c.502COT c.563AOG p.Arg168Cys/ p.Asn188Ser Missense Compound heterozygous K C C (diffuse) Octreotide K 12 Died Exon 10 c.1598TOC p.Leu533Pro Missense Homozygous K C K Died Novel mutation 13 10.6 Exon 5/ exon 21 c.694TOG/ c.2525GOA p.Trp232Gly/ p.Arg842Gln Missense/ Missense Compound heterozygous K C K Octreotide CC 14 5.5 Exon 12 c.1771TOC p.Phe591Leu Missense Heterozygous C K Diazoxide K KCNJ11 15 2.4 Exon 1 c.101GOA/ c.376GOA p.Arg34His/ p.Glu126Lys Missense/ Missense Compound heterozygous K C K Octreotide K 16 3.3 Exon 1 c.272GOA p.Trp91X Nonsense Homozygous K C C (diffuse) Octreotide CC 17 3.2 Exon 1 c.376GOA p.Glu126Lys Missense Homozygous K C C (diffuse) Octreotide CC HADH 18 4.4 Exon 6 c.706COT p.Arg236X Nonsense Homozygous C Diazoxide C Genotype-phenotype correlation " Comparison between KATP mutation-positive and KATP mutation-negative groups highlighted a statistically significant increased birth weight and younger age of presentation in KATP mutation-positive group as compared with KATP mutation-negative patients (Table 3).
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ABCC8 p.Asn188Ser 24686051:85:1168
status: NEW