ABCMdb

ABCC8 p.Gln485His

Predicted by SNAP2:	A: D (66%), C: D (75%), D: D (85%), E: D (75%), F: D (80%), G: D (80%), H: D (75%), I: D (66%), K: D (80%), L: D (71%), M: D (75%), N: D (75%), P: D (91%), R: D (59%), S: D (53%), T: N (53%), V: D (66%), W: D (75%), Y: D (71%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia. 2012 Jan;55(1):123-7. Epub 2011 Oct 12. Bowman P, Flanagan SE, Edghill EL, Damhuis A, Shepherd MH, Paisey R, Hattersley AT, Ellard S
Heterozygous ABCC8 mutations are a cause of MODY.
Diabetologia. 2012 Jan;55(1):123-7. Epub 2011 Oct 12., [PMID:21989597]

Abstract [show]
AIMS/HYPOTHESIS: The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic beta cell ATP-sensitive potassium (K(ATP)) channel. Inactivating mutations cause congenital hyperinsulinism (CHI) and activating mutations cause transient neonatal diabetes (TNDM) or permanent neonatal diabetes (PNDM) that can usually be treated with sulfonylureas. Sulfonylurea sensitivity is also a feature of HNF1A and HNF4A MODY, but patients referred for genetic testing with clinical features of these types of diabetes do not always have mutations in the HNF1A/4A genes. Our aim was to establish whether mutations in the ABCC8 gene cause MODY that is responsive to sulfonylurea therapy. METHODS: We sequenced the ABCC8 gene in 85 patients with a BMI <30 kg/m(2), no family history of neonatal diabetes and who were deemed sensitive to sulfonylureas by the referring clinician or were sulfonylurea-treated. All had tested negative for mutations in the HNF1A and HNF4A genes. RESULTS: ABCC8 mutations were found in seven of the 85 (8%) probands. Four patients were heterozygous for previously reported mutations and four novel mutations, E100K, G214R, Q485R and N1245D, were identified. Only four probands fulfilled MODY criteria, with two diagnosed after 25 years and one patient, who had no family history of diabetes, as a result of a proven de novo mutation. CONCLUSIONS/INTERPRETATION: ABCC8 mutations can cause MODY in patients whose clinical features are similar to those with HNF1A/4A MODY. Therefore, sequencing of ABCC8 in addition to the known MODY genes should be considered if such features are present, to facilitate optimal clinical management of these patients.

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No. Sentence Comment
61 The Q485R mutation arose de novo in proband 6 and is novel, although a different mutation at this residue, Q485H, has been reported in a patient with PNDM [10]. Login to comment
62 Two of the novel mutations, N1245D and E100K (probands 4 and 7), were inherited from a diabetic parent but grandparental samples were not available to check cosegregation. Login to comment
66 The Q485R mutation arose de novo in proband 6 and is novel, although a different mutation at this residue, Q485H, has been reported in a patient with PNDM [10]. Login to comment

[hide] Molecular diagnosis of neonatal diabetes mellitus ... PLoS One. 2010 Oct 26;5(10):e13630. Bonnefond A, Durand E, Sand O, De Graeve F, Gallina S, Busiah K, Lobbens S, Simon A, Bellanne-Chantelot C, Letourneau L, Scharfmann R, Delplanque J, Sladek R, Polak M, Vaxillaire M, Froguel P
Molecular diagnosis of neonatal diabetes mellitus using next-generation sequencing of the whole exome.
PLoS One. 2010 Oct 26;5(10):e13630., [PMID:21049026]

Abstract [show]
BACKGROUND: Accurate molecular diagnosis of monogenic non-autoimmune neonatal diabetes mellitus (NDM) is critical for patient care, as patients carrying a mutation in KCNJ11 or ABCC8 can be treated by oral sulfonylurea drugs instead of insulin therapy. This diagnosis is currently based on Sanger sequencing of at least 42 PCR fragments from the KCNJ11, ABCC8, and INS genes. Here, we assessed the feasibility of using the next-generation whole exome sequencing (WES) for the NDM molecular diagnosis. METHODOLOGY/PRINCIPAL FINDINGS: We carried out WES for a patient presenting with permanent NDM, for whom mutations in KCNJ11, ABCC8 and INS and abnormalities in chromosome 6q24 had been previously excluded. A solution hybridization selection was performed to generate WES in 76 bp paired-end reads, by using two channels of the sequencing instrument. WES quality was assessed using a high-resolution oligonucleotide whole-genome genotyping array. From our WES with high-quality reads, we identified a novel non-synonymous mutation in ABCC8 (c.1455G>C/p.Q485H), despite a previous negative sequencing of this gene. This mutation, confirmed by Sanger sequencing, was not present in 348 controls and in the patient's mother, father and young brother, all of whom are normoglycemic. CONCLUSIONS/SIGNIFICANCE: WES identified a novel de novo ABCC8 mutation in a NDM patient. Compared to the current Sanger protocol, WES is a comprehensive, cost-efficient and rapid method to identify mutations in NDM patients. We suggest WES as a near future tool of choice for further molecular diagnosis of NDM cases, negative for chr6q24, KCNJ11 and INS abnormalities.

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Sentences [show]
No. Sentence Comment
6 From our WES with high-quality reads, we identified a novel non-synonymous mutation in ABCC8 (c.1455G.C/p.Q485H), despite a previous negative sequencing of this gene. Login to comment
59 Unexpectedly, we identified a novel heterozygous non-synonymous mutation c.1455G.C/p.Q485H in the 9th exon of ABCC8. Login to comment
61 In both cases, we identified the p.Q485H mutation in ABCC8, confirming our WES results. Login to comment
62 In addition, retrospective re-examination of the data generated six years ago indicated that the p.Q485H mutation was present in the original ABCC8 exon 9 sequences (chromogram). Login to comment
63 The ABCC8 p.Q485H mutation was not found in 348 French nondiabetic individuals or in the patient`s mother, father and young brother, all of whom are normoglycemic. Login to comment
64 The p.Q485H mutation affects an amino acid that is located in the transmembrane domain 1 (TMD1) of the ABCC8/SUR1 core; and that is highly conserved across species (Rhesus, Mouse, Dog, Rabbit, Elephant, Opossum, Platypus, Chicken, Lizard, Stickleback, X_Tropicalis, Tetraodon) according to the UCSC (NCBI/hg18) comparative genomics alignment pipeline (http://www.bx.psu. Login to comment
66 We evaluated the possible functional significance of the p.Q485H mutation by the PolyPhen-2 (Polymorphism Phenotyping v2) software which uses sequenceand structure-based criteria to predict the putative impact of point mutations on the structure and function of human proteins [8]: the p.Q485H mutation is predicted 'probably damaging` with a score of 0.999 (the score of 1 indicating the most damaging mutation). Login to comment
78 The p.Q485H mutation was missed six years ago by the research assistant in charge of the sequence reading. Login to comment
87 We are quite confident that the p.Q485H mutation is likely to be functional given the non ambiguous prediction of its putative damaging effect. Login to comment
114 Mutation validation The p.Q485H mutation identified via WES was confirmed using the Sanger method. Login to comment
57 Unexpectedly, we identified a novel heterozygous non-synonymous mutation c.1455G.C/p.Q485H in the 9th exon of ABCC8. Login to comment
60 In addition, retrospective re-examination of the data generated six years ago indicated that the p.Q485H mutation was present in the original ABCC8 exon 9 sequences (chromogram). Login to comment
76 The p.Q485H mutation was missed six years ago by the research assistant in charge of the sequence reading. Login to comment
85 We are quite confident that the p.Q485H mutation is likely to be functional given the non ambiguous prediction of its putative damaging effect. Login to comment
112 Mutation validation The p.Q485H mutation identified via WES was confirmed using the Sanger method. Login to comment