ABCMdb

ABCC8 p.Asp1471Asn

ClinVar:	c.4411G>A , p.Asp1471Asn D , Likely pathogenic
Predicted by SNAP2:	A: D (66%), C: D (71%), E: D (63%), F: D (75%), G: D (75%), H: D (63%), I: D (80%), K: D (80%), L: D (75%), M: D (71%), N: N (72%), P: D (91%), Q: D (63%), R: D (80%), S: D (66%), T: D (71%), V: D (75%), W: D (85%), Y: D (75%),
Predicted by PROVEAN:	A: D, C: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[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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6 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). Login to comment
7 SUR1 G228D and D1471N singly or in combination led to intracellular retention of the channel complex and loss of function. Login to comment
30 There is also a notation based on a potential splice variant of 1582 amino acids in length.19 The SUR1 mutations,D1193V and R1436Q (referred to as SUR1D1193V/R1436Q), and G228D and D1471 (referred to as SUR1G228D/D1471N),were made in the same SUR1 cDNA construct to mimic the fact that the patients had mutations on the same chromosome.Mouse Kir6·2 was used and expressed as described previously.41 Mouse Kir6·2-GFP (Kir6·2 fused in frame with the enhanced variant of the green fluorescent protein) and Kir6·2-HA (Kir6·2 engineered to contain an extracellular antigenic haemagglutinin epitope tag between the first transmembrane domain and the H5 segment) were kind gifts of Drs Ribalet and Jan, respectively. Login to comment
76 4411 g > a, leading to the amino acid change G228D and D1471N. Login to comment
97 By contrast, SUR1G228D, SUR1D1471N and SUR1G228D/D1471N all failed to translocate Kir6·2-GFP to the plasma membrane. Login to comment
98 SURV1572I translocated Kir6·2-GFP to the plasma membrane (Fig. 2b).We confirmed that Kir6·2-GFP was located in the ER when expressed with one of the SUR1 mutants (SUR1G228D/D1471N) that could not deliver a complex to the membrane by colocalizing with DsRed2-ER (Fig. 2c). Login to comment
99 In addition, we performed quantitative colocalization analysis as described previously, measuring the fraction of green pixels (Kir6·2-GFP) that also contain red (DsRed2-ER).45 In some representative images Kir6·2-GFP = 89 ± 5% (n = 7), SUR1 + Kir6·2-GFP = 31 ± 6% (n = 5) and SUR1G228D/D1471N + Kir6·2-GFP = 82 ± 2% (n = 6, P < 0·001 vs. SUR1 + Kir6·2-GFP and not significant vs. Kir6·2-GFP). Login to comment
105 By contrast, SUR1G228D, SUR1D1471N and SUR1G228D/D1471N all failed to translocate Kir6·2-HA to the surface of the cell (Fig. 3c). Login to comment
114 SUR1D1193V and SUR1V1572I were functional in Rb86 flux assays whereas SUR1R1436Q, SUR1D1193V/R1436Q,SUR1G228D,SUR1D1471NandSUR1G228D/ D1471N were not (Fig. 4). Login to comment
120 SUR1D1193V, SUR1V1572I and SUR1D1471N were functional in patch clamp assays whereas SUR1R1436Q, SUR1D1193V/R1436Q, SUR1G228D and SUR1G228D/D1471N were not.In the knowledge of these results we repeated the flux assays and trafficking assays with Kir6·2-GFP with SUR1D1471N. Login to comment
123 Finally, we mimicked the complex genotype in the patient in the second family by coexpressing SUR1V1572I and SUR1G228D/ D1471N together with Kir6·2-GFP (Fig. 6a) or Kir6·2 (Fig. 6b). Login to comment
125 In addition, the expression of SUR1V1572I with SUR1G228D/D1471N and Kir6·2 led to a recovery of function as indicated by substantial Rb+ fluxes (Fig. 6b). Login to comment
137 (c) Representative confocal images of HEK293 cells transiently transfected with Kir6·2-GFP, DsRed2-ER and SUR1G228D/D1471N. Login to comment
145 In contrast to the first family, mutations expressed singly or in combination (SUR1G228D,SUR1D1471N and SUR1G228D/D1471N) led to a degree of loss of function due to the failure of the channel complex to traffic. Login to comment
146 The mutations SUR1G228D and SUR1G228D/ D1471N were unambiguous in that in all the assays used, the mutant channel complexes failed to traffic and were nonfunctional. Login to comment
158 The disease in patient 2 arose because of paternal inheritance of SUR1G228D/D1471N and a focal somatic event,and in contrast to patient 1,both mutations singly or in combination are deficient in trafficking and function. Login to comment

[hide] Case report: pathological features of aberrant pan... Ann Clin Lab Sci. 2008 Autumn;38(4):386-9. Brunetti-Pierri N, Olutoye OO, Heptulla R, Tatevian N
Case report: pathological features of aberrant pancreatic development in congenital hyperinsulinism due to ABCC8 mutations.
Ann Clin Lab Sci. 2008 Autumn;38(4):386-9., [PMID:18988933]

Abstract [show]
We describe a patient with congenital hyperinsulinism with previously unreported pathological findings including normal to decreased number of insulin-positive cells with very few enlarged nuclei, aberrant distribution of glucagon-positive cells, and a non-insulin producing adenomatous focus of unusual morphology. Molecular analysis showed that the patient was a compound heterozygote for two mutations of the ABCC8 gene: a previously unreported nonsense mutation (R841X) and a missense mutation (D1471N) that has been previously described. This case suggests that abnormal function of ABCC8 may result in aberrant pancreatic development.

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2 Molecular analysis showed that the patient was a compound heterozygote for two mutations of the ABCC8 gene: a previously unreported nonsense mutation (R841X) and a missense mutation (D1471N) that has been previously described. Login to comment
54 Complete sequence information was obtained for all 38 amplicons and revealed a C>T change at nucleotide position 2521 leading to a premature stop codon at position 841 Annals of Clinical & Laboratory Science, vol. 38, no. 4, 2008388 (R841X) and a G>A change at nucleotide position 4411 resulting in the substitution of aspartate with asparagine at codon 1471 (D1471N). Login to comment
57 Discussion In our patient, molecular analysis of the ABCC8 gene confirmed the clinical and pathological diagnosis of the diffuse form of congenital hyperinsulinism and revealed the presence of two distinct mutations: a novel nonsense mutation (R841X) and a missense mutation (D1471N) that was previously reported by Sharma et al [6]). Login to comment
52 Complete sequence information was obtained for all 38 amplicons and revealed a C>T change at nucleotide position 2521 leading to a premature stop codon at position 841 Annals of Clinical & Laboratory Science, vol. 38, no. 4, 2008 (R841X) and a G>A change at nucleotide position 4411 resulting in the substitution of aspartate with asparagine at codon 1471 (D1471N). Login to comment
55 Discussion In our patient, molecular analysis of the ABCC8 gene confirmed the clinical and pathological diagnosis of the diffuse form of congenital hyperinsulinism and revealed the presence of two distinct mutations: a novel nonsense mutation (R841X) and a missense mutation (D1471N) that was previously reported by Sharma et al [6]). 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