ABCMdb

PMID: 9648840

Shyng SL, Ferrigni T, Shepard JB, Nestorowicz A, Glaser B, Permutt MA, Nichols CG
Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy.
Diabetes. 1998 Jul;47(7):1145-51., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCC8 p.Asn188Ser ABCC8 p.Phe591Leu ABCC8 p.His125Gln We have studied the functional properties of novel SUR1 mutations identified in PHHI patients, including H125Q, N188S, F591L, T1139M, R1215Q, G1382S, and R1394H. Login to comment 3 ABCC8 p.Asn188Ser ABCC8 p.Phe591Leu ABCC8 p.His125Gln R1394H and F1388 SUR1, a previously identified PHHI mutation, resulted in no functional channels when coexpressed with Kir6.2 in COS cells, while H125Q, N188S, F591L, T1139M, R1215Q, and G1382S SUR1 generated functional channels in the absence of ATP. Login to comment 4 ABCC8 p.Asn188Ser ABCC8 p.His125Gln With the exception of N188S and H125Q, all mutants had reduced response to stimulation by MgADP. Login to comment 75 ABCC8 p.Asn188Ser ABCC8 p.Phe591Leu ABCC8 p.His125Gln The positions of the seven newly identified SUR1 mutations that are associated with the disease PHHI are shown in Fig. 1, including H125Q, N188S, F591L, T1139M, R1215Q, G1382S, and R1394H on both SUR1 topology models. Login to comment 90 ABCC8 p.Phe591Leu ABCC8 p.His125Gln The level of activity of other channels follows the order of WT ~N188S ~T1139M > G1382S > H125Q > F591L > R1215Q. Login to comment 102 ABCC8 p.Phe591Leu Figure 5A illustrates the response ofmutant channels toMgADP.Inwild-type channels, MgADP stimulated channel activity in the presence of inhibitory ATP, and this stimulatory effect was reduced in mutant F591L, T1139M, R1215Q, and G1382S (Fig. 5B). Login to comment 112 ABCC8 p.Asn188Ser ABCC8 p.Phe591Leu ABCC8 p.His125Gln Compared with wild-type channels, H125Q had a slightlygreater response to diazoxide (P < 0.1, ANOVA), N188S hada response that is similar to the wild-type channel (NS, ANOVA), T1139M and G1382S mutant channels had slightly reduced responses, while F591L and R1215Q channels had severely reduced responses (P < 0.005 and 0.025, respectively, ANOVA) (Fig. 6). Login to comment 124 ABCC8 p.Phe591Leu Only F591L shows slightly increased ATP sensitivity (n = 3-8). Login to comment 131 ABCC8 p.His125Gln Another patient, compound heterozygous for the H125Q mutation and the F1388 mutation, had clinically mild disease. Login to comment 132 ABCC8 p.His125Gln The mild disease is consistent with the functional data of the H125Q mutation. Login to comment 138 ABCC8 p.Asn188Ser One patient was homozygous for the N188S mutation and another compound heterozygousforthis mutation and a novel splice-site mutation 3992-3 c-to-g (M.A.P., B.G., unpublished observations). Login to comment 141 ABCC8 p.Phe591Leu The first had relatively mild disease andwas diazoxide-responsive even though the in vitro data on this mutation (F591L) might predict a more severe disease. Login to comment 156 ABCC8 p.Asn188Ser ABCC8 p.His125Gln With the exception of N188S and H125Q, which formed channels that were indistinguishable from the wild-type in terms of regulation of the channel by nucleotides and diazoxide, all other mutants caused defects of various severity in the resulting channels. Login to comment 158 ABCC8 p.Phe591Leu F591L, T1139M, R1215Q, and G1382S all showed a reduced response to stimulation by MgADP. Login to comment 162 ABCC8 p.His125Gln Although for some mutations ( F1388, H125Q, R1215Q, R1394H) the in vitro findings correlate well with the clinical observations, in other mutations there seems to be a discrepancy between in vitro and clinical observations. Login to comment 163 ABCC8 p.Asn188Ser This is particularly true of the N188S mutation, which alters channel function only minimally in vitro but is associated with severe clinical disease. Login to comment 166 ABCC8 p.Phe591Leu For two mutations, F591L and G1382S, it was not possible to correlate the in vitro and clinical characteristics, since the patients with these mutations were heterozygous with no mutation identified onthe second allele. Login to comment 173 ABCC8 p.Gly716Val Previously identified PHHI missense SUR1 mutations were all positioned within the two nucleotide-binding folds, including G1479R (11), F1388 (23), and G716V (25). Login to comment 175 ABCC8 p.Asn188Ser ABCC8 p.Phe591Leu ABCC8 p.His125Gln Five others (H125Q, N188S, F591L, T1139M, and R1215Q) are outside of the predicted nucleotide-binding folds. Login to comment 176 ABCC8 p.Asn188Ser ABCC8 p.His125Gln However, except for N188S and H125Q, these mutations all show some defects in regulation of the channel by MgADP or by diazoxide. Login to comment 183 ABCC8 p.Asn188Ser ABCC8 p.Asn188Ser 1150 DIABETES, VOL. 47, JULY 1998 SUR1 MUTATIONS AND KATP CHANNELS TABLE 1 Clinical characteristics of the PHHI patients bearing SUR1 mutations Clinical Diazoxide Patient Allele 1 Allele 2 Onset severity responsiveness Treatment G2,4 F1388 F1388 <1 week Severe No Octreotide H2 N188S N188S ?? Login to comment 185 ABCC8 p.Asn188Ser ABCC8 p.Phe591Leu ABCC8 p.His125Gln Pancreatectomy BV N188S 3992-3 c-to-g <1 week Severe No Pancreatectomy CB H125Q F1388 1 year Mild No Pancreatectomy Q R1215Q 3992-9 g-to-a <1 week Severe Inadequate Pancreatectomy AO R1394H 3992-9 g-to-a < week Severe No Pancreatectomy BI F591L - <1 week Mild Yes Diazoxide BU G1382S - <1 week Severe ?? Login to comment