ABCC8 p.Ala1263Thr
| Predicted by SNAP2: | C: N (78%), D: D (71%), E: D (71%), F: D (59%), G: N (87%), H: D (63%), I: N (57%), K: D (71%), L: N (53%), M: N (66%), N: D (63%), P: D (66%), Q: D (63%), R: D (66%), S: N (87%), T: N (61%), V: N (57%), W: D (59%), Y: D (63%), |
| Predicted by PROVEAN: | C: D, D: D, E: D, F: D, G: N, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: D, S: N, T: N, V: D, W: D, Y: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Clinical and molecular characterisation of 300 pat... Eur J Endocrinol. 2013 Mar 15;168(4):557-64. doi: 10.1530/EJE-12-0673. Print 2013 Apr. Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K
Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism.
Eur J Endocrinol. 2013 Mar 15;168(4):557-64. doi: 10.1530/EJE-12-0673. Print 2013 Apr., [PMID:23345197]
Abstract [show]
BACKGROUND: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI. AIM: To characterise the clinical and molecular aspects of a large cohort of patients with CHI. METHODOLOGY: Three hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A). RESULTS: Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3). CONCLUSIONS: A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.
Comments [show]
None has been submitted yet.
No. Sentence Comment
94 Two of these (patients 97 and 270) are heterozygous for the same novel mutation (p.A1263T).
X
ABCC8 p.Ala1263Thr 23345197:94:83
status: NEW[hide] Clinical and histological heterogeneity of congeni... Eur J Endocrinol. 2014 Dec;171(6):685-95. doi: 10.1530/EJE-14-0353. Epub 2014 Sep 8. Arya VB, Guemes M, Nessa A, Alam S, Shah P, Gilbert C, Senniappan S, Flanagan SE, Ellard S, Hussain K
Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations.
Eur J Endocrinol. 2014 Dec;171(6):685-95. doi: 10.1530/EJE-14-0353. Epub 2014 Sep 8., [PMID:25201519]
Abstract [show]
CONTEXT: Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported. OBJECTIVE: The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. DESIGN: A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted. RESULTS: Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 l-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography 18F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (n=8) or 18F DOPA-PET CT (n=27). Diffuse, indeterminate and focal disease was identified in 13, 1 and 21 patients respectively. Two patients with suspected diffuse disease were identified to have focal disease on histology. CONCLUSIONS: Paternally inherited heterozygous ABCC8/KCNJ11 mutations can manifest as a wide spectrum of CHI with variable 18F DOPA-PET CT/histological findings and clinical outcomes. Focal disease was histologically confirmed in 24/53 (45%) of CHI patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations.
Comments [show]
None has been submitted yet.
No. Sentence Comment
70 (c.1629-2A>C) Walker B *R177W *M209I *I284del E292K T294M G312C COOH COOH NH2 M1 M2 6 1 TMD0 TMD1 TMD2 2 3 4 5 7 8 9 10 11 12 13 14 15 16 17 p.*391Rext*94 *T62M R1494W Q954X G111R A113V *V601I *A1153T D1031N L1171X A1263T V185fs Intracellular NH2 NBD2 NBD1 Cell membrane Figure 1 Paternal mutations mapped onto the SUR1 and Kir6.2 protein.
X
ABCC8 p.Ala1263Thr 25201519:70:215
status: NEW76 p.?/N (c.1333-1013AOG/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 42 37, 4480 Female !1 1.7 5.6 A1263T/N (c.3787GOA/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 45 39, 3960 Male !1 2.4 23.6 p.?/N (c.1-?_c.1176C1?/N) No Focal Hypoglycaemia resolved after removal of focal lesion 46 34, 3800 Male !1 0.8 201 D855E/N (c.2565COA/N) No Focal Hypoglycaemia resolved after removal of focal lesion 47 41, 4780 Male !1 2.4 15.9 M429X/N (c.1254_1284dup/N) No Focal Hypoglycaemia resolved after removal of focal lesion 48 40, 3800 Female !1 2.4 5.9 M429X/N (c.1254_1284dup/N) No Diffuse On octreotide at 7 months 49 40, 4100 Male !1 0.8 9.1 R74W/N (c.220COT/N) No Focal Hypoglycaemia resolved after removal of focal lesion 51 38, 3730 Female !1 1.9 21.6 E995X (c.2983GOT) No Focal Hypoglycaemia resolved after removal of focal lesion KCNJ11 7 38, 3780 Female !1 1.7 29.6 M209I/N (c.627GOA/N) Yes Diffuse On Dzx at 2.8 years 12 40, 3450 Male !1 2 6.7 R54H/N (c.161GOA/N) Yes - Off Dzx after 4 months 26 36, 3880 Male !1 !1.0 6.1 E292K/N (c.874GOA/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 28 40, 4600 Male !1 1.3 38.87 R136fs/N (c.405dupG/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 35 38, 4120 Female !1 2.2 12.0 T294M/N (c.881COT/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 36 37, 3960 Male !1 1.9 7.0 G312C/N (c.934GOT/N) No Focal Hypoglycaemia resolved after removal of focal lesion 43 40, 4100 Female !1 1.0 35 I284del/N (c.850_852delATC/N) Yes Diffuse Off Dzx at 4 years of age 44 40, 4580 Female 32 2.2 7 p.*391Rext*94/N (c.1171TO C/N) No Focal Partial pancreatectomy, currently on Dzx 50 37, 3980 Male !1 0.5 2.9 T62M/N (c.185COT/N) Yes - Off Dzx at 1 month 52 40, 5190 Male !1 2.5 8.4 R177W/N (c.529AOT/N) Yes Diffuse On Dzx at 3 months of age 53 40, 3920 Male !1 2.1 9.2 E292K/N (c.874GOA/N) Yes Diffuse Off Dzx at 5 months of age Dzx, diazoxide; PET, positron emission tomography; PVS, pancreatic venous sampling; GA, gestational age; Wt, weight; LOH, loss of heterozygosity; Resp, responsiveness.
X
ABCC8 p.Ala1263Thr 25201519:76:121
status: NEW