ABCMdb

ABCC8 p.Val1572Ile

ClinVar:	c.4714G>A , p.Val1572Ile N , Benign
Predicted by SNAP2:	A: D (63%), C: D (53%), D: D (80%), E: D (71%), F: D (63%), G: D (66%), H: D (53%), I: N (61%), K: D (71%), L: D (63%), M: D (53%), N: D (71%), P: D (75%), Q: D (53%), R: D (71%), S: D (80%), T: N (53%), W: D (71%), Y: D (63%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, W: D, Y: D,

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Publications
[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
8 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. Login to comment
86 It is pertinent to note that V1572I has previously been reported to be a polymorphism, on the basis that it is a conservative amino acid substitution, in an Askenazi Jewish population but has not been studied functionally.19 Trafficking and expression studies We first examined the potential subcellular distribution of the Kir6·2/ SUR1 mutant channel complexes. Login to comment
155 The SUR1G228D and SUR1D1471N mutations are paternally inherited; however,the situation is further complicated by the potential inheritance of a maternal DNA variation (SUR1V1572I).V1573I (alternative notation) has been reported to be a polymorphism on the basis that it is a conservative amino acid and found in controls with a low frequency.19,40 V1572I/V1573I has,however,not been studied functionally and a potential impact was not excluded a priori. Login to comment