ABCC8 p.Thr1531Ala
| Predicted by SNAP2: | A: D (80%), C: D (80%), D: D (91%), E: D (91%), F: D (85%), G: D (85%), H: D (85%), I: D (85%), K: D (91%), L: D (91%), M: D (85%), N: D (85%), P: D (91%), Q: D (85%), R: D (91%), S: D (75%), V: D (85%), W: D (91%), Y: D (85%), |
| 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, R: D, S: 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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No. Sentence Comment
11 Altogether, 16 different ABCC8 mutations (including the novel alterations W231R, C267X, IVS6-3C.G, I462V, Q917X and T1531A) were identified.
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ABCC8 p.Thr1531Ala 19475716:11:116
status: NEW106 Six of the ABCC8 mutations (W231R, C267X, IVS6-3C.G, I462V, Q917X, and T1531A) were novel, whereas the remaining have been previously reported and in several cases functionally characterized (Table 2).
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ABCC8 p.Thr1531Ala 19475716:106:71
status: NEW122 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.
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ABCC8 p.Thr1531Ala 19475716:122:201
status: NEW131 In families Hypo-N11 and Hypo-N19, the mutations G1478R and T1531A occurred de novo as they were not seen in blood samples from the parents.
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ABCC8 p.Thr1531Ala 19475716:131:60
status: NEW133 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.
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ABCC8 p.Thr1531Ala 19475716:133:795
status: NEW142 This proband had an IVS1011G.T mutation inherited from the mother and a de novo T1531A mutation likely to have arisen on the paternal allele.
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ABCC8 p.Thr1531Ala 19475716:142:80
status: NEW173 Three novel variants (W231R, I462V, and T1531A) are missense mutations.
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ABCC8 p.Thr1531Ala 19475716:173:40
status: NEW177 The mutations I462V and T1531A, however, are positioned outside the TMD and NBD of SUR1 and have lower PSIC scores.
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ABCC8 p.Thr1531Ala 19475716:177:24
status: NEW181 Concerning T1531A, it must have occurred de novo on the paternal chromosome of the affected child, assuming that the disease in family Hypo-N19 was inherited recessively.
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ABCC8 p.Thr1531Ala 19475716:181:11
status: NEW182 This would predict T1531A to be pathogenic.
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ABCC8 p.Thr1531Ala 19475716:182:19
status: NEW