ABCC8 p.Gln485Arg
| 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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[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
7 Four patients were heterozygous for previously reported mutations and four novel mutations, E100K, G214R, Q485R and N1245D, were identified.
X
ABCC8 p.Gln485Arg 21989597:7:106
status: NEW58 Four mutations are novel (E100K, G214R, Q485R and N1245D) and affect residues conserved across species, and none were present in the dbSNP (November 2010) or 1000 genomes databases (May 2011).
X
ABCC8 p.Gln485Arg 21989597:58:40
status: NEW61 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].
X
ABCC8 p.Gln485Arg 21989597:61:4
status: NEW62 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.
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ABCC8 p.Gln485Arg 21989597:62:467
status: NEW73 N/M 19 SU 50s Family 1 R1380H/N Family 2 R1380H/N 50s OHA 21 Ins 40s OHA N/M 33 SU N/M 11 SU N/M 18 SU SB Family 3 V222M/G214R V222M/N 45 V222M/G214R 15 Ins Family 4 N1245D/N Family 6 Q485R/N Family 5 V1523L/N Family 7 E100K/N N/M 36 SU N/M 14 Ins N/M 40s OHA 60s Diet N/M 13 SU N/N N/N N/M 42 OHA & Ins N/N 60s Diet N/M 60s Diet ×2 SU Fig. 1 Partial pedigrees showing affected family members, genetic status and treatment (where known).
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ABCC8 p.Gln485Arg 21989597:73:184
status: NEW81 The Q485R mutation is highly likely to be pathogenic since it has arisen de novo and a different mutation at this residue has been reported previously [10].
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ABCC8 p.Gln485Arg 21989597:81:4
status: NEW92 The de novo Q485R mutation highlights the fact that a family history of diabetes is not a prerequisite for monogenic diabetes and alerts the patient to the 50% risk of diabetes in her future offspring.
X
ABCC8 p.Gln485Arg 21989597:92:12
status: NEW63 Four mutations are novel (E100K, G214R, Q485R and N1245D) and affect residues conserved across species, and none were present in the dbSNP (November 2010) or 1000 genomes databases (May 2011).
X
ABCC8 p.Gln485Arg 21989597:63:40
status: NEW66 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].
X
ABCC8 p.Gln485Arg 21989597:66:4
status: NEW78 N/M 19 SU 50s Family 1 R1380H/N Family 2 R1380H/N 50s OHA 21 Ins 40s OHA N/M 33 SU N/M 11 SU N/M 18 SU SB Family 3 V222M/G214R V222M/N 45 V222M/G214R 15 Ins Family 4 N1245D/N Family 6 Q485R/N Family 5 V1523L/N Family 7 E100K/N N/M 36 SU N/M 14 Ins N/M 40s OHA 60s Diet N/M 13 SU N/N N/N N/M 42 OHA & Ins N/N 60s Diet N/M 60s Diet &#d7;2 SU Fig. 1 Partial pedigrees showing affected family members, genetic status and treatment (where known).
X
ABCC8 p.Gln485Arg 21989597:78:184
status: NEW86 The Q485R mutation is highly likely to be pathogenic since it has arisen de novo and a different mutation at this residue has been reported previously [10].
X
ABCC8 p.Gln485Arg 21989597:86:4
status: NEW97 The de novo Q485R mutation highlights the fact that a family history of diabetes is not a prerequisite for monogenic diabetes and alerts the patient to the 50% risk of diabetes in her future offspring.
X
ABCC8 p.Gln485Arg 21989597:97:12
status: NEW