ABCC8 p.Pro1413Leu
| Predicted by SNAP2: | A: N (78%), C: N (61%), D: N (61%), E: N (57%), F: D (66%), G: N (97%), H: D (59%), I: D (63%), K: N (66%), L: N (57%), M: D (59%), N: N (82%), Q: N (78%), R: N (66%), S: N (93%), T: N (82%), V: N (61%), W: D (71%), Y: D (66%), |
| 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, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] The Knudson's two-hit model and timing of somatic ... J Clin Endocrinol Metab. 2006 Oct;91(10):4118-23. Epub 2006 Aug 1. Giurgea I, Sempoux C, Bellanne-Chantelot C, Ribeiro M, Hubert L, Boddaert N, Saudubray JM, Robert JJ, Brunelle F, Rahier J, Jaubert F, Nihoul-Fekete C, de Lonlay P
The Knudson's two-hit model and timing of somatic mutation may account for the phenotypic diversity of focal congenital hyperinsulinism.
J Clin Endocrinol Metab. 2006 Oct;91(10):4118-23. Epub 2006 Aug 1., [PMID:16882742]
Abstract [show]
BACKGROUND: Congenital hyperinsulinism (CHI) is associated with focal hyperplasia of endocrine tissue in 40-65% of patients. Focal CHI is sporadic and is caused by a germline, paternally inherited, mutation of the SUR1 (ABCC8) or KIR6.2 (KCNJ11) genes (encoding subunits of the pancreatic ATP-dependent potassium channel) together with somatic maternal haploinsufficiency for 11p15.5. Plurifocal or large forms of focal CHI are a cause of apparent failure of surgery, and their underlying mechanism has not been thoroughly investigated. PATIENTS: We here report two patients with bifocal CHI as evidenced by relapsing hypoglycemia after removal of the first focal lesion and the detection of a second, distinct, focal adenomatous hyperplasia during later surgery (patients 1 and 2) and a patient with a giant focal lesion involving the major part of the pancreas (patient 3). RESULTS: In the three patients, a germline, paternally inherited, mutation of SUR1 was found. In patients 1 and 2, haploinsufficiency for the maternal 11p15.5 region resulted from a somatic deletion specific for each of the focal lesions, as shown by the diversity of deletion break points. In patient 3, an identical somatic maternal 11p15 deletion demonstrated by similar break points was shown in two independent lesion samples, suggesting a very early event during pancreas embryogenesis. CONCLUSION: Individual patients with focal hyperinsulinism may have more than one focal pancreatic lesion due to separate somatic maternal deletion of the 11p15 region. These patients and those with solitary focal lesions may follow the two-hit model described by Knudson. The stage of embryogenesis at which the somatic event occurs may account for the observed histological diversity (early event giant lesion, later event small lesion).
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83 In addition, all three patients had a heterozygous, paternally inherited SUR1 (ABCC8) gene mutation (patient 1, c.3988 ϩ 2_ϩ15del14; patient 2, R598X; patient 3, P1413L).
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ABCC8 p.Pro1413Leu 16882742:83:174
status: NEW[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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122 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.Pro1413Leu 19475716:122:286
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.Pro1413Leu 19475716:133:653
status: NEW168 A largenumber (.150)ofABCC8 alterations have been reported to cause CHI (19) including 10 of the mutations observed in this study (V21D, V187D, R248X, E490X, L503P, IVS1011G.T, G1400R, P1413L, G1478R, and R1493W).
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ABCC8 p.Pro1413Leu 19475716:168:185
status: NEW