ABCMdb

ABCC8 p.Val222Met

Predicted by SNAP2:	A: N (82%), C: N (93%), D: D (80%), E: D (71%), F: D (63%), G: D (75%), H: D (71%), I: N (72%), K: D (71%), L: N (66%), M: D (66%), N: D (75%), P: D (75%), Q: D (71%), R: D (66%), S: N (57%), T: N (82%), W: D (80%), Y: D (75%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: N, T: N, 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
53 The PCR products were subsequently sequenced to reveal whether the G214R and V222M mutations were on the same or opposite alleles. Login to comment
58 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). Login to comment
64 In proband 3, in whom two mutations were identified, allele specific PCR demonstrated that the G214R and V222M mutations were inherited on the paternal and maternal alleles, respectively. Login to comment
65 Since the V222M mutation has previously been seen in a patient with hyperinsulinism (S. Ellard and S. Flanagan, unpublished data), G214R cannot be an inactivating mutation as this would result in a hyperinsulinism phenotype and not diabetes. Login to comment
73 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). Login to comment
59 V222M known CHI 15 20 27.3 Insulin. Login to comment
69 In proband 3, in whom two mutations were identified, allele specific PCR demonstrated that the G214R and V222M mutations were inherited on the paternal and maternal alleles, respectively. Login to comment
70 Since the V222M mutation has previously been seen in a patient with hyperinsulinism (S. Ellard and S. Flanagan, unpublished data), G214R cannot be an inactivating mutation as this would result in a hyperinsulinism phenotype and not diabetes. Login to comment
78 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). Login to comment