ABCMdb

ABCC8 p.Glu1323Lys

Predicted by SNAP2:	A: N (57%), C: N (61%), D: N (53%), F: D (59%), G: D (59%), H: N (66%), I: N (57%), K: D (53%), L: N (72%), M: N (61%), N: N (61%), P: D (59%), Q: N (72%), R: D (53%), S: N (61%), T: N (72%), V: N (57%), W: D (59%), Y: D (53%),
Predicted by PROVEAN:	A: D, C: D, D: 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, T: D, V: D, W: D, Y: D,

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Publications
[hide] Co-inheritance of two ABCC8 mutations causing an u... Gene. 2013 Mar 1;516(1):122-5. doi: 10.1016/j.gene.2012.12.055. Epub 2012 Dec 22. Faletra F, Snider K, Shyng SL, Bruno I, Athanasakis E, Gasparini P, Dionisi-Vici C, Ventura A, Zhou Q, Stanley CA, Burlina A
Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: clinical and functional characterization of two novel ABCC8 mutations.
Gene. 2013 Mar 1;516(1):122-5. doi: 10.1016/j.gene.2012.12.055. Epub 2012 Dec 22., [PMID:23266803]

Abstract [show]
Congenital hyperinsulinism (CHI) occurs as a consequence of unregulated insulin secretion from the pancreatic beta-cells. Severe recessive mutations and milder dominant mutations have been described in the ABCC8 and KCNJ11 genes encoding SUR1 and Kir6.2 subunits of the beta-cell ATP-sensitive K(+) channel. Here we report two patients with CHI unresponsive to medical therapy with diazoxide. Sequencing analysis identified a compound heterozygous mutation in ABCC8 in both patients. The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Functional studies of both novel alleles showed reduced or null cell surface expression, typical of recessive mutations. Compound heterozygous mutations in congenital hyperinsulinism result in complex interactions. Studying these mechanisms can improve the knowledge of this disease and modify its therapy.

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No. Sentence Comment
4 The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. Login to comment
5 The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Login to comment
72 The second heterozygous mutation was the p.Glu1323Lys; c.3967G>A. Login to comment
74 The p.Glu1323Lys change is a novel mutation, not included in either online database as a polymorphism or as a known disease-causing mutation. Login to comment
77 A pedigree of family and compound heterozygosity of the patient 1, formed by the p.Glu1506Lys mutation (in gray), inherited from his father and also present in the paternal aunt and paternal grandmother, and the p.Glu1323Lys mutation (in black), inherited from the mother and maternal grandmother. Login to comment
79 The worst condition of the patient 1 compared to other patients with the p.Glu1506Lys mutation could be due to the simultaneous inheritance of this and the p.Glu1323Lys mutation. Login to comment
80 Patient 2 was heterozygous for the same novel p.Glu1323Lys mutation. Login to comment
88 As Fig. 2A shows neither the E1323K nor the M1394R mutants are glycosylated appropriately in comparison to the WT, indicating that these mutants probably cause trafficking defects and are likely retained in the endoplasmic reticulum. Login to comment
92 The E1323K mutant Fig. 2. Login to comment
94 COSm6 cells were co-transfected with cDNAs for Kir6.2 and WT-flagSUR1, the M1394R-flagSUR1 or the E1323K-flagSUR1. Login to comment
97 (B) Both mutants show reduced cell surface expression, although the E1323K mutant retains some surface expression (16.98&#b1;4.87%; n=3). Login to comment
99 (A) The E1323K mutant shows similar MgADP response (69.16&#b1;5.42%; n=8) as WT channels (76.87&#b1;6.80%; n=7). Login to comment
104 The percent of current for WT and E1323K was (70.31&#b1;8.62%; n=8) and (54.12&#b1;10.71%; n=5), respectively. Login to comment
106 In inside-out patch-clamp electrophysiological recordings, small currents were detected in cells expressing the E1323K mutant (relative to WT; see Figs. Login to comment
108 Moreover, channel responses to the metabolic regulator magnesium adenosine diphosphate (MgADP) (Fig. 3A) and the channel agonist diazoxide (Fig. 3B) were evaluated for the E1323K mutant. Login to comment
109 The E1323K mutant exhibited similar responses to both MgADP and diazoxide as WT channels in the presence of inhibitory ATP (0.1 mM). Login to comment
116 In patient 2, who is compound heterozygous for the p.[Glu1323Lys]: [Met1394Arg] mutations, both defects seem to have a recessive inheritance and impair the channel trafficking to the plasma membrane, even though E1323K does have normal gating properties. Login to comment

[hide] Sirolimus Therapy in Congenital Hyperinsulinism: A... Pediatrics. 2015 Nov;136(5):e1373-6. doi: 10.1542/peds.2015-1132. Minute M, Patti G, Tornese G, Faleschini E, Zuiani C, Ventura A
Sirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience Beyond Infancy.
Pediatrics. 2015 Nov;136(5):e1373-6. doi: 10.1542/peds.2015-1132., [PMID:26504125]

Abstract [show]
Congenital hyperinsulinism (CHI) due to diffuse involvement of the pancreas is a challenging and severe illness in children. Its treatment is based on chronic therapy with diazoxide and/or octreotide, followed by partial pancreatectomy, which is often not resolutive. Sirolimus, a mammalian target of rapamycin inhibitor, was reported to be effective in treating CHI in infants. We report here the case of an 8-year-old boy affected by a severe form of CHI due to a biallelic heterozygous ABCC8 mutation who responded to sirolimus with a dramatic improvement in his glucose blood level regulation and quality of life, with no serious adverse events after 6 months of follow-up. To the best of our knowledge, this is the first report of a successful intervention in an older child. It provides a promising basis for further studies comparing sirolimus with other treatments, particularly in older children.

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Sentences [show]
No. Sentence Comment
16 He was diagnosed with a double heterozygous ABCC8 biallelic mutation (E1323K/E1506K), encoding for the SUR1 subunit of the potassium channel; 18 F-L- dihydroxyphenylalanine positron emission tomography revealed diffuse pancreatic involvement, with no sign of focal lesions. Login to comment