ABCMdb

ABCC8 p.Arg1493Trp

Predicted by SNAP2:	A: D (91%), C: D (85%), D: D (95%), E: D (91%), F: D (95%), G: D (91%), H: D (85%), I: D (91%), K: D (80%), L: D (91%), M: D (91%), N: D (85%), P: D (91%), Q: D (85%), S: D (85%), T: D (85%), V: D (91%), W: D (91%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] The spectrum of ABCC8 mutations in Norwegian patie... Clin Genet. 2009 May;75(5):440-8. Sandal T, Laborie LB, Brusgaard K, Eide SA, Christesen HB, Sovik O, Njolstad PR, Molven A
The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy.
Clin Genet. 2009 May;75(5):440-8., [PMID:19475716]

Abstract [show]
Potassium channels in the plasma membrane of the pancreatic beta cells are critical in maintaining glucose homeostasis by responding to ATP and coupling metabolic changes to insulin secretion. These channels consist of subunits denoted the sulfonylurea receptor SUR1 and the inwardly rectifying ion channel KIR6.2, which are encoded by the genes ABCC8 and KCNJ11, respectively. Activating mutations in the subunit genes can result in monogenic diabetes, whereas inactivating mutations are the most common cause of congenital hyperinsulinism of infancy (CHI). Twenty-six Norwegian probands with CHI were analyzed for alterations in ABCC8 and KCNJ11. Fifteen probands (58%) had mutations in the ABCC8 gene. Nine patients were homozygous or compound heterozygous for the mutations, indicating diffuse pancreatic disease. In five patients, heterozygous and paternally inherited mutations were found, suggesting focal disease. One patient had a de novo mutation likely to cause a milder, dominant form of CHI. Altogether, 16 different ABCC8 mutations (including the novel alterations W231R, C267X, IVS6-3C>G, I462V, Q917X and T1531A) were identified. The mutations IVS10+1G>T, R1493W and V21D occurred in five, three and two families, respectively. KCNJ11 mutations were not found in any patients. Based on our mutation screening, we estimate the minimum birth prevalence of ABCC8-CHI in Norway to 1:70,000 during the past decade. Our results considerably extend the knowledge of the molecular genetics behind CHI in Scandinavia.

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12 The mutations IVS1011G.T, R1493W and V21D occurred in five, three and two families, respectively. Login to comment
107 The mutations IVS1011G.T, R1493W and V21D were recurrent mutations as they were observed in five, three and two independently recruited families, respectively. Login to comment
109 Clinical characteristics of Norwegian CHI patients carrying mutations in ABCC8 Proband Sex Birth weight (g)/gestation length (weeks)a Treatment Mutationsd Medicalb Surgeryc Maternal chromosome Paternal chromosome Hypo-N3 F 6190/38 Deceased Yes (S) R1493W R1493W Hypo-N6 M 5340/38 Somatostatin, diet (FM, PEG) No V21D V21D Hypo-N8 F 5740/37 Insulin Yes (S) G1400R R1493W Hypo-N9 F 5130/40 Diet (FM) Yes (S) - IVS1011G.T Hypo-N11 M 4000/38 None No - G1478Re Hypo-N14 M 5000/40 Somatostatin, diet (FM, PEG) No - IVS1011G.T Hypo-N16 F 3780/38 Diet (FM) No - C267X Hypo-N19 F 5240/40 Somatostatin, diet (FM, PEG) No IVS1011G.T T1531Af Hypo-N22 M 4500/39 Diazoxide Yes (S) IVS6-3C.G, I462V Q917X Hypo-N23 F 4860/38 Insulin Yes (S) P1413Lg IVS1011G.Tg Hypo-N25 M 3910/34 Insulin Yes (S) V21Dg E490Xg Hypo-N26 M 3790/35 Diet (FM, PEG) Yes (H) V187D R248X Hypo-N29 F 3350/37 None Yes (P) - IVS1011G.T Hypo-N30 F 3800/37 Diazoxide No W231R L503P Hypo-N31 M 4340/40 None Yes (P) - R1493W a All cases had birth weights 12 standard deviation scores except for Hypo-N29 whose score was 11. b Current therapy is given. Login to comment
122 We classified the mutations as either MnMn Hypo-N3 R1493W MMMM Mn Mn Hypo-N6 V21D MM MnMn Hypo-N8 G1400R / R1493W MM nnMn Hypo-N9 IVS10 Mn Hypo-N11 G1478R Mn nnMn Hypo-N16 C267X Mn Mn Hypo-N19 IVS10 / T1531A MM Mn nn Hypo-N29 IVS10 Mn Mn Hypo-N30 W231R / L503P MM MM x Hypo-N23 IVS10 / P1413L MM x Hypo-N14 IVS10 Mn Hypo-N22 IVS6 (I462V) / Q917X MM Hypo-N25 V21D / E490X MM xx Hypo-N26 V187D / R248 X MM x Hypo-N31 R1493W nnMnMnMn nnnnMn MnMn MM MnMn Mn nnnn Fig. 1. Login to comment
133 ABCC8 mutations found in Norwegian CHI patientsa Nucleotide change Location Amino acid change Mutation type PSIC score PD Number of families Reference c.62 T.A Exon 1 V21D Mis 1.96 PoD 2 (24) c.560 T.A Exon 4 V187D Mis 2.01 PrD 1 (2) c.691 T.C Exon 5 W231R Mis 4.03 PrD 1 NR c.742 C.T Exon 5 R248X Non - - 1 (34, 42) c.801 C.A Exon 5 C267X Non - - 1 NR IVS6-3C.G Intron 6 - AS - - 1 NR c.1384 A.G Exon 9 I462V Mis 0.62 PrB 1 NR c.1468 G.T Exon 10 E490X Non - - 1 (43) c.1508 T.C Exon 10 L503P Mis 2.36 PrD 1 (24) IVS1011G.T Intron 10 - AS - - 5 (44) c.2749 C.T Exon 23 Q917X Non - - 1 NR c.4198 G.A Exon 35 G1400R Mis 2.37 PrD 1 (42) c.4238 C.T Exon 35 P1413L Mis 2.76 PrD 1 (25) c.4432 G.A Exon 37 G1478R Mis 2.37 PrD 1 (14, 31) c.4477 C.T Exon 37 R1493W Mis 2.79 PrD 3 (26) c.4591 A.G Exon 38 T1531A Mis 1.93 PoD 1 NR AS, aberrant splicing; Mis, missense; NR, not previously reported; Non, nonsense; PD, pathogenic description; PoD, possibly damaging; PrB, predicted to be benign; PrD, probably damaging; PSIC, position-specific independent counts. Login to comment
168 A largenumber (.150)ofABCC8 alterations have been reported to cause CHI (19) including 10 of the mutations observed in this study (V21D, V187D, R248X, E490X, L503P, IVS1011G.T, G1400R, P1413L, G1478R, and R1493W). Login to comment

[hide] Functional hot spots in human ATP-binding cassette... Protein Sci. 2010 Nov;19(11):2110-21. Kelly L, Fukushima H, Karchin R, Gow JM, Chinn LW, Pieper U, Segal MR, Kroetz DL, Sali A
Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains.
Protein Sci. 2010 Nov;19(11):2110-21., [PMID:20799350]

Abstract [show]
The human ATP-binding cassette (ABC) transporter superfamily consists of 48 integral membrane proteins that couple the action of ATP binding and hydrolysis to the transport of diverse substrates across cellular membranes. Defects in 18 transporters have been implicated in human disease. In hundreds of cases, disease phenotypes and defects in function can be traced to nonsynonymous single nucleotide polymorphisms (nsSNPs). The functional impact of the majority of ABC transporter nsSNPs has yet to be experimentally characterized. Here, we combine experimental mutational studies with sequence and structural analysis to describe the impact of nsSNPs in human ABC transporters. First, the disease associations of 39 nsSNPs in 10 transporters were rationalized by identifying two conserved loops and a small alpha-helical region that may be involved in interdomain communication necessary for transport of substrates. Second, an approach to discriminate between disease-associated and neutral nsSNPs was developed and tailored to this superfamily. Finally, the functional impact of 40 unannotated nsSNPs in seven ABC transporters identified in 247 ethnically diverse individuals studied by the Pharmacogenetics of Membrane Transporters consortium was predicted. Three predictions were experimentally tested using human embryonic kidney epithelial (HEK) 293 cells stably transfected with the reference multidrug resistance transporter 4 and its variants to examine functional differences in transport of the antiviral drug, tenofovir. The experimental results confirmed two predictions. Our analysis provides a structural and evolutionary framework for rationalizing and predicting the functional effects of nsSNPs in this clinically important membrane transporter superfamily.

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50 Disease-associated nsSNPs at Three Structural Hotspots in Human ABC Transporter NBDs Gene Disease Position ARA motif ABCB11 BRIC2 A570T ABCD1 X-ALD A616V CFTR CF A559T ABCC6 PXE R765Q ABCC8 HHF1 R841G ABCC8 HHF1 R1493Q ABCC8 HHF1 R1493W ABCD1 X-ALD R617C ABCD1 X-ALD R617G ABCD1 X-ALD R617H CFTR CF R560K CFTR CF R560S CFTR CF R560T ABCA1 HDLD1 A1046D ABCB4 ICP A546D C-loop 1 motif ABCC8 HHF1 D1471H ABCC8 HHF1 D1471N CFTR CBAVD G544V ABCC8 HHF1 G1478R C-loop2 motif ABCA4 STGD1 H2128R ABCC8 HHF1 K889T ABCD1 X-ALD R660P ABCD1 X-ALD R660W ABCA1 HDLD2 M1091T ABCA4 STGD1 E2131K ABCA12 LI2 E1539K ABCA4 STGD1 and CORD3 E1122K CFTR CF L610S ABCC8 HHF1 L1543P ABCA1 Colorectal cancer sample; somatic mutation A2109T ABCC9 CMD1O A1513T ABCD1 X-ALD H667D CFTR CF A613T ABCA1 HDLD2 D1099Y ABCD1 X-ALD T668I CFTR CF D614G ABCA4 STGD1 R2139W ABCA4 STGD1 R1129C ABCA4 ARMD2, STGD1, and FFM R1129L Disease abbreviations are as follows: BRIC2, benign recurrent intrahepatic cholestasis type 2; X-ALD, X-linked adrenoleukodystrophy; CF, cystic fibrosis; PXE, Pseudoxanthoma elasticum; HHF1, familial hyperinsulinemic hypoglycemia-1; HDLD1, high density lipoprotein deficiency type 1; ICP, intrahepatic cholestasis of pregnancy; CBAVD, congenital bilateral absence of the vas deferens; STGD1, Stargardt disease type 1; HDLD2, high density lipoprotein deficiency type 2; LI2, ichthyosis lamellar type 2; CORD3, cone-rod dystrophy type 3; CMD1O, cardiomyopathy dilated type 1O; ARMD2, age-related macular degeneration type 2; FFM, fundus flavimaculatus. Login to comment

[hide] Congenital hyperinsulinism: clinical and molecular... Gene. 2013 May 25;521(1):160-5. doi: 10.1016/j.gene.2013.03.021. Epub 2013 Mar 16. Faletra F, Athanasakis E, Morgan A, Biarnes X, Fornasier F, Parini R, Furlan F, Boiani A, Maiorana A, Dionisi-Vici C, Giordano L, Burlina A, Ventura A, Gasparini P
Congenital hyperinsulinism: clinical and molecular analysis of a large Italian cohort.
Gene. 2013 May 25;521(1):160-5. doi: 10.1016/j.gene.2013.03.021. Epub 2013 Mar 16., [PMID:23506826]

Abstract [show]
Congenital hyperinsulinism (CHI) is a genetic disorder characterized by profound hypoglycemia related to an inappropriate insulin secretion. It is a heterogeneous disease classified into two major subgroups: "channelopathies" due to defects in ATP-sensitive potassium channel, encoded by ABCC8 and KCNJ11 genes, and "metabolopathies" caused by mutation of several genes (GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) and involved in different metabolic pathways. To elucidate the genetic etiology of CHI in the Italian population, we conducted an extensive sequencing analysis of the CHI-related genes in a large cohort of 36 patients: Twenty-nine suffering from classic hyperinsulinism (HI) and seven from hyperinsulinism-hyperammonemia (HI/HA). Seventeen mutations have been found in fifteen HI patients and five mutations in five HI/HA patients. Our data confirm the major role of ATP-sensitive potassium channel in the pathogenesis of Italian cases (~70%) while the remaining percentage should be attributed to other. A better knowledge of molecular basis of CHI would lead to improve strategies for genetic screening and prenatal diagnosis. Moreover, genetic analysis might also help to distinguish the two histopathological forms of CHI, which would lead to a clear improvement in the treatment and in genetic counseling.

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119 HI-group mutations identified Patient E/I nt changea aa changea Zygosity/inheritance References (A) Genetic variants found in ABCC8, KCNJ11, HNF4A and GCK genes from HI-group ABCC8 (NM_000352.3) 21 E 10 c.1580_1581dup p.Lys528Glyfs*4 Heterozygosity/paternal Present study 29 E 10 c.1617T>A p.Tyr539* Heterozygosity/ND Present study 24 E 16 c.2146G>A p.Gly716Ser Heterozygosity/ND Present study 13 E 23 c.2780G>A p.Trp927* Heterozygosity/ND Present studyb 20 E 24 c.2857C>T p.Gln953* Heterozygosity/ND Nestorowicz et al. (1998) 20 I 32 c.3989-2A>G Aberrant splicing Heterozygosity/ND Present study 19 E 35 c.4278_4280dup p.Gln1426_Asp1427insGlu Heterozygosity/ND Present study 15,25 E 36 c.4356delinsTA p.Glu1452Aspfs*61 Heterozygosity/paternal Present study 8 E 37 c.4477C>T p.Arg1493Trp Heterozygosity/ND Verkarre et al. (1998) 3 E 37 c.4516G>A p.Glu1506Lys Heterozygosity/maternal Huopio et al. (2000) 28 E 39 c.4684C>G p.Pro1562Ala Heterozygosity/ND Present study KCNJ11 (NM_000525.3) 7 E 1 c.151G>T p.Glu51* Heterozygosity/ND Present study 6 E 1 c.1017G>T p.Val339Val Heterozygosity/paternal Present study HNF4A (NM_000457.3) 27 E 5 c.511G>A p.Gly171Arg Heterozygosity/maternal Present study GCK (NM_000162.3) 6 E 1 c.31G>A p.Ala11Thr Heterozygosity/paternal Chiu et al. (1993) 12 E 6 c.600G>A p.Val200Val Heterozygosity/ND Present study (B) Genetic variants found in GLUD1 gene from HI/HA-group GLUD1 (NM_005271.3) 33 E 7 c.943C>T p.His315Tyr Heterozygosity/de novo Halldorsdottir et al. (2000) 35 E 7 c.955T>C p.Tyr319His Heterozygosity/ND Stanley (2004) 30 E 10 c.1387A>T p.Asn463Tyr Heterozygosity/ND Present study 36 E 11 c.1493C>T p.Ser498Leu Heterozygosity/ND Stanley et al. (1998) 31 E 12 c.1498G>A p.Ala500Thr Heterozygosity/maternal Stanley et al. (2000) E = exon; I = intron.; ND = not determined. Login to comment