ABCC8 p.Asp1193Val
| Predicted by SNAP2: | A: N (78%), C: D (53%), E: N (72%), F: D (63%), G: N (87%), H: N (66%), I: D (63%), K: D (71%), L: D (63%), M: D (66%), N: N (93%), P: D (59%), Q: N (72%), R: N (57%), S: N (93%), T: N (82%), V: D (66%), W: D (71%), Y: N (57%), |
| Predicted by PROVEAN: | A: D, C: D, E: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: D, S: N, 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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No. Sentence Comment
3 Results The first case had diffuse disease and was homozygous for the mutations D1193V and R1436Q in SUR1.
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ABCC8 p.Asp1193Val 17466004:3:80
status: NEW4 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.
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ABCC8 p.Asp1193Val 17466004:4:33
status: NEW30 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.
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ABCC8 p.Asp1193Val 17466004:30:113
status: NEW64 He was homozygous for two mutations in SUR1, namely D1193V and R1436Q, with both mutations occurring on each allele.
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ABCC8 p.Asp1193Val 17466004:64:52
status: NEW129 The mutation D1193V introduced alone into SUR1 led Fig. 2 The trafficking and expression of SUR1 mutants.
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ABCC8 p.Asp1193Val 17466004:129:13
status: NEW[hide] Congenital hyperinsulinism: clinical and molecular... Int J Pediatr Endocrinol. 2014;2014(1):24. doi: 10.1186/1687-9856-2014-24. Epub 2014 Dec 15. Arya VB, Aziz Q, Nessa A, Tinker A, Hussain K
Congenital hyperinsulinism: clinical and molecular characterisation of compound heterozygous ABCC8 mutation responsive to Diazoxide therapy.
Int J Pediatr Endocrinol. 2014;2014(1):24. doi: 10.1186/1687-9856-2014-24. Epub 2014 Dec 15., [PMID:25584046]
Abstract [show]
BACKGROUND: Mutations in ABCC8 and KCNJ11 are the most common cause of congenital hyperinsulinism (CHI). Recessive as well as dominant acting ABCC8/KCNJ11 mutations have been described. Diazoxide, which is the first line medication for CHI, is usually ineffective in recessive ABCC8 mutations. We describe the clinical and molecular characterisation of a recessive ABCC8 mutation in a CHI patient that is diazoxide response. CLINICAL CASE: A term macrosomic female infant presented with symptomatic persistent hypoglycaemia confirmed to be secondary to CHI. She exhibited an excellent response to moderate doses of diazoxide (10 mg/kg/day). Molecular genetic analysis of the proband confirmed a biallelic ABCC8 mutation - missense R526C inherited from an unaffected mother and a frameshift c.1879delC mutation (H627Mfs*20) inherited from an unaffected father. Follow-up highlighted persistent requirement for diazoxide to control CHI. Functional analysis of mutants confirmed them to result in diazoxide-responsive CHI, consistent with the clinical phenotype. CONCLUSION: Biallelic ABCC8 mutations may result in diazoxide-responsive CHI. Irrespective of the molecular genetic analysis results, accurate assessment of the response to diazoxide should be undertaken before classifying a patient as diazoxide-responsive or unresponsive CHI.
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No. Sentence Comment
83 Muzyamba et al. showed that single SUR1 mutants (D1193V or R1436Q) trafficked to the plasma membrane whereas the double mutant (SUR1D1193V/ R1436Q) was retained in the endoplasmic reticulum [16].
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ABCC8 p.Asp1193Val 25584046:83:49
status: NEW