ABCMdb

PMID: 12110524

Huopio H, Shyng SL, Otonkoski T, Nichols CG
K(ATP) channels and insulin secretion disorders.
Am J Physiol Endocrinol Metab. 2002 Aug;283(2):E207-16., [PubMed]

Sentences

No. Mutations Sentence Comment

65 ABCC8 p.Glu1506Lys ABCC8 p.Phe591Leu Reduced sensitivity to stimulation by MgADP is a defect of channels generated by a number of HI-associated SUR1 mutations, including F591L, T1139M, R1215Q, G1382S, and E1506K (25, 59) (Fig. 1B). Login to comment 68 ABCC8 p.Arg1420Cys One HI mutation (SUR1[R1420C]) lowers the affinity of NBF2 for ATP and ADP and abolishes the cooperative binding between the two NBFs (36). Login to comment 71 ABCC8 p.Arg1420Cys Consistent with the biochemical data, the EC50 for MgADP activation of the SUR1[R1420C] af9; Kir6.2[R50G] mutant channel is about three times higher than that of wild-type SUR1 af9; Kir6.2[R50G] channels. Login to comment 76 ABCC8 p.Glu1506Lys ABCC8 p.Phe591Leu Reduced sensitivity to stimulation by MgADP is a defect of channels generated by a number of HI-associated SUR1 mutations, including F591L, T1139M, R1215Q, G1382S, and E1506K (25, 59) (Fig. 1B). Login to comment 79 ABCC8 p.Arg1420Cys One HI mutation (SUR1[R1420C]) lowers the affinity of NBF2 for ATP and ADP and abolishes the cooperative binding between the two NBFs (36). Login to comment 82 ABCC8 p.Arg1420Cys Consistent with the biochemical data, the EC50 for MgADP activation of the SUR1[R1420C] ϩ Kir6.2[R50G] mutant channel is about three times higher than that of wild-type SUR1 ϩ Kir6.2[R50G] channels. Login to comment 123 ABCC8 p.Val187Asp The recessively inherited missense mutation V187D, located in a transmembrane domain of SUR1, leads to severe early-onset HI (46). Login to comment 125 ABCC8 p.Val187Asp Interestingly, the disease phenotype is almost as severe in patients homozygous or heterozygous for the mutation; even a single copy of the V187D mutation seems to lead to a severe drug-unresponsive form of HI in compound heterozygotes. Login to comment 127 ABCC8 p.Val187Asp ABCC8 p.Val187Asp Functional studies (intact cell recordings, cell-free inside-out patches) of beta-cells isolated from an HI patient homozygous for the V187D mutation, as well as the results of recombinant KATP channel experiments, are consistent with the phenotype and show that mutation SUR1[V187D] leads to a loss of functional KATP channels that are not activated by diazoxide or somatostatin. Login to comment 128 ABCC8 p.Glu1506Lys The dominantly inherited mutation SUR1(E1506K) (Fig. 3B) associates with a different phenotype (25). Login to comment 130 ABCC8 p.Glu1506Lys This clinical finding is in agreement with the results of coexpression studies of recombinant wild-type (wt)-Kir6.2 and SUR1[E1506K]. Login to comment 132 ABCC8 p.Glu1506Lys Despite the dominant nature of SUR1[E1506K] in causing the disease, it does not exert a completely dominant negative effect when expressed together with the wild-type gene in Xenopus oocytes. Login to comment 133 ABCC8 p.Glu1506Lys Studies of glucose homeostasis in carriers of the SUR1[E1506K] mutation have indicated that this mutation leads to insulin deficiency and to development of diabetes mellitus in later life (25). Login to comment 134 ABCC8 p.Val187Asp The recessively inherited missense mutation V187D, located in a transmembrane domain of SUR1, leads to severe early-onset HI (46). Login to comment 136 ABCC8 p.Val187Asp Interestingly, the disease phenotype is almost as severe in patients homozygous or heterozygous for the mutation; even a single copy of the V187D mutation seems to lead to a severe drug-unresponsive form of HI in compound heterozygotes. Login to comment 138 ABCC8 p.Val187Asp ABCC8 p.Val187Asp Functional studies (intact cell recordings, cell-free inside-out patches) of beta-cells isolated from an HI patient homozygous for the V187D mutation, as well as the results of recombinant KATP channel experiments, are consistent with the phenotype and show that mutation SUR1[V187D] leads to a loss of functional KATP channels that are not activated by diazoxide or somatostatin. Login to comment 139 ABCC8 p.Glu1506Lys The dominantly inherited mutation SUR1(E1506K) (Fig. 3B) associates with a different phenotype (25). Login to comment 141 ABCC8 p.Glu1506Lys This clinical finding is in agreement with the results of coexpression studies of recombinant wild-type (wt)-Kir6.2 and SUR1[E1506K]. Login to comment 143 ABCC8 p.Glu1506Lys Despite the dominant nature of SUR1[E1506K] in causing the disease, it does not exert a completely dominant negative effect when expressed EINVITED REVIEW AJP-Endocrinol Metab • VOL 283 • AUGUST 2002 • www.ajpendo.org together with the wild-type gene in Xenopus oocytes. Login to comment 144 ABCC8 p.Glu1506Lys Studies of glucose homeostasis in carriers of the SUR1[E1506K] mutation have indicated that this mutation leads to insulin deficiency and to development of diabetes mellitus in later life (25). Login to comment 153 ABCC8 p.Glu1506Lys ABCC8 p.Val187Asp Birthplaces of parents of HI patients with founder mutations SUR1(E1506K) (E) and SUR1(V187D) (F) are indicated (8, 40). Login to comment 154 ABCC8 p.Glu1506Lys B: pedigree and haplotype analysis of a large Finnish pedigree carrying the SUR1(E1506K) mutation. Login to comment 157 ABCC8 p.Glu1506Lys The haplotype 3-4-4 associates with E1506K in all cases. Login to comment 164 ABCC8 p.Glu1506Lys ABCC8 p.Val187Asp Birthplaces of parents of HI patients with founder mutations SUR1(E1506K) (E) and SUR1(V187D) (F) are indicated (8, 40). Login to comment 165 ABCC8 p.Glu1506Lys B: pedigree and haplotype analysis of a large Finnish pedigree carrying the SUR1(E1506K) mutation. Login to comment 168 ABCC8 p.Glu1506Lys The haplotype 3-4-4 associates with E1506K in all cases. Login to comment