ABCMdb

PMID: 21989597

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., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC8 p.Gln485Arg ABCC8 p.Gly214Arg ABCC8 p.Glu100Lys Four patients were heterozygous for previously reported mutations and four novel mutations, E100K, G214R, Q485R and N1245D, were identified. Login to comment 52 ABCC8 p.Gly214Arg Briefly, primers were designed to amplify a single copy of the patient`s ABCC8 gene using a primer complementary to the G214R mutation (primer sequences available on request). Login to comment 53 ABCC8 p.Gly214Arg ABCC8 p.Val222Met 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 ABCC8 p.Gln485Arg ABCC8 p.Gly214Arg ABCC8 p.Gly214Arg ABCC8 p.Gly214Arg ABCC8 p.Glu100Lys ABCC8 p.Val222Met ABCC8 p.Val222Met 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 59 ABCC8 p.Val222Met V222M known CHI 15 20 27.3 Insulin. Login to comment 60 ABCC8 p.Thr229Ile ABCC8 p.Val1523Leu ABCC8 p.Val1523Leu V1523L (proband 5) was previously identified in a patient with PNDM who was a compound heterozygote for V1523L and T229I [5]. Login to comment 61 ABCC8 p.Gln485Arg ABCC8 p.Gln485His 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 ABCC8 p.Val1523Leu ABCC8 p.Gln485Arg ABCC8 p.Glu100Lys ABCC8 p.Glu100Lys ABCC8 p.Gln485His 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 63 ABCC8 p.Gln485Arg ABCC8 p.Gly214Arg ABCC8 p.Glu100Lys 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 ABCC8 p.Gly214Arg ABCC8 p.Val222Met 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 ABCC8 p.Thr229Ile ABCC8 p.Val1523Leu ABCC8 p.Val1523Leu ABCC8 p.Gly214Arg ABCC8 p.Val222Met 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 66 ABCC8 p.Gln485Arg ABCC8 p.Gln485His 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 67 ABCC8 p.Glu100Lys 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 69 ABCC8 p.Gly214Arg ABCC8 p.Val222Met 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 ABCC8 p.Gly214Arg ABCC8 p.Val222Met 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 ABCC8 p.Val1523Leu ABCC8 p.Gln485Arg ABCC8 p.Gly214Arg ABCC8 p.Gly214Arg ABCC8 p.Glu100Lys ABCC8 p.Val222Met ABCC8 p.Val222Met ABCC8 p.Val222Met 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 78 ABCC8 p.Val1523Leu ABCC8 p.Gln485Arg ABCC8 p.Gly214Arg ABCC8 p.Gly214Arg ABCC8 p.Glu100Lys ABCC8 p.Val222Met ABCC8 p.Val222Met ABCC8 p.Val222Met 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 81 ABCC8 p.Gln485Arg 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]. Login to comment 82 ABCC8 p.Glu100Lys The evidence for pathogenicity of the E100K and N1245D mutations is less certain, and both probands progressed from gliclazide to insulin therapy. Login to comment 86 ABCC8 p.Gln485Arg 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]. Login to comment 87 ABCC8 p.Glu100Lys The evidence for pathogenicity of the E100K and N1245D mutations is less certain, and both probands progressed from gliclazide to insulin therapy. Login to comment 92 ABCC8 p.Gln485Arg 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. Login to comment 97 ABCC8 p.Gln485Arg 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. Login to comment