ABCC8 p.Gly228Asp
| Predicted by SNAP2: | A: N (82%), C: N (72%), D: N (61%), E: N (57%), F: N (61%), H: N (61%), I: N (57%), K: D (53%), L: N (57%), M: N (57%), N: N (72%), P: N (57%), Q: N (78%), R: D (53%), S: N (93%), T: N (78%), V: N (72%), W: D (75%), Y: N (53%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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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
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).
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ABCC8 p.Gly228Asp 17466004:6:121
status: NEW7 SUR1 G228D and D1471N singly or in combination led to intracellular retention of the channel complex and loss of function.
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ABCC8 p.Gly228Asp 17466004:7:5
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.Gly228Asp 17466004:30:171
status: NEW76 4411 g > a, leading to the amino acid change G228D and D1471N.
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ABCC8 p.Gly228Asp 17466004:76:45
status: NEW[hide] ABCC8 and KCNJ11 molecular spectrum of 109 patient... J Med Genet. 2010 Nov;47(11):752-9. Epub 2010 Aug 3. Bellanne-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, Arnoux JB, Valayannopoulos V, Gobrecht S, Sempoux C, Rahier J, Fournet JC, Jaubert F, Aigrain Y, Nihoul-Fekete C, de Lonlay P
ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.
J Med Genet. 2010 Nov;47(11):752-9. Epub 2010 Aug 3., [PMID:20685672]
Abstract [show]
BACKGROUND: Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic beta-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. METHODS: ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. RESULTS: ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. CONCLUSIONS: The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.
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103 1 DH c-htz This report ABCC8 Exon 5 c.655C/T p.Gln219X 2 DPET, DPVS c-htz;htzP Flanagan et al, 200817 ABCC8 Exon 5 c.683G/A p.Gly228Asp 1 FH Flanagan et al, 200817 ABCC8 Exon 5 c.727_756del30 p.Lys243_Lys252del 1 DH hmz This report ABCC8 Exon 5 c.742C/T p.Arg248X 1 DPET hmz Flanagan et al, 200817 ABCC8 Exon 6 c.950delC p.Pro317fs 1 DPET c-htz This report ABCC8 Exon 7 c.1176G/A p.?
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ABCC8 p.Gly228Asp 20685672:103:126
status: NEW106 1 FH This report ABCC8 Exon 14 c.2035_2036insCTGT p.Val679fs 1 DH hmz This report ABCC8 Exon 15 c.2051G/A p.Gly684Glu 1 FH This report ABCC8 Exon 15 c.2064G/A p.Trp688X 1 FH Giurgea et al, 200446 ABCC8 Intron 15 c.2116+2T/C p.?
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ABCC8 p.Gly228Asp 20685672:106:126
status: NEW