ABCMdb

PMID: 23266803

Faletra F, Snider K, Shyng SL, Bruno I, Athanasakis E, Gasparini P, Dionisi-Vici C, Ventura A, Zhou Q, Stanley CA, Burlina A
Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: clinical and functional characterization of two novel ABCC8 mutations.
Gene. 2013 Mar 1;516(1):122-5. doi: 10.1016/j.gene.2012.12.055. Epub 2012 Dec 22., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCC8 p.Glu1506Lys ABCC8 p.Glu1323Lys The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. Login to comment 5 ABCC8 p.Glu1323Lys ABCC8 p.Met1394Arg The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Login to comment 70 ABCC8 p.Glu1506Lys The first one was the known dominant mutation p.Glu1506Lys; c.4516G>A (Huopio et al., 2002). Login to comment 72 ABCC8 p.Glu1323Lys The second heterozygous mutation was the p.Glu1323Lys; c.3967G>A. Login to comment 74 ABCC8 p.Glu1323Lys The p.Glu1323Lys change is a novel mutation, not included in either online database as a polymorphism or as a known disease-causing mutation. Login to comment 75 ABCC8 p.Glu1506Lys The p.Glu1506Lys mutation has been reported in several families and causes a dominant CHI well controlled by diazoxide (Huopio et al., 2003). Login to comment 76 ABCC8 p.Glu1506Lys Although there is still controversy on this issue, p.Glu1506Lys has been suggested to Fig. 1. Login to comment 77 ABCC8 p.Glu1506Lys ABCC8 p.Glu1323Lys A pedigree of family and compound heterozygosity of the patient 1, formed by the p.Glu1506Lys mutation (in gray), inherited from his father and also present in the paternal aunt and paternal grandmother, and the p.Glu1323Lys mutation (in black), inherited from the mother and maternal grandmother. Login to comment 79 ABCC8 p.Glu1506Lys ABCC8 p.Glu1323Lys The worst condition of the patient 1 compared to other patients with the p.Glu1506Lys mutation could be due to the simultaneous inheritance of this and the p.Glu1323Lys mutation. Login to comment 80 ABCC8 p.Glu1323Lys Patient 2 was heterozygous for the same novel p.Glu1323Lys mutation. Login to comment 81 ABCC8 p.Met1394Arg In addition he has a novel variant, p.Met1394Arg (c.4181T>G). Login to comment 85 ABCC8 p.Glu1506Lys Functional analysis was previously performed on the p.Glu1506Lys mutation (Vieira et al., 2010). Login to comment 88 ABCC8 p.Glu1323Lys ABCC8 p.Met1394Arg As Fig. 2A shows neither the E1323K nor the M1394R mutants are glycosylated appropriately in comparison to the WT, indicating that these mutants probably cause trafficking defects and are likely retained in the endoplasmic reticulum. Login to comment 92 ABCC8 p.Glu1323Lys The E1323K mutant Fig. 2. Login to comment 94 ABCC8 p.Glu1323Lys ABCC8 p.Met1394Arg COSm6 cells were co-transfected with cDNAs for Kir6.2 and WT-flagSUR1, the M1394R-flagSUR1 or the E1323K-flagSUR1. Login to comment 97 ABCC8 p.Glu1323Lys (B) Both mutants show reduced cell surface expression, although the E1323K mutant retains some surface expression (16.98&#b1;4.87%; n=3). Login to comment 99 ABCC8 p.Glu1323Lys (A) The E1323K mutant shows similar MgADP response (69.16&#b1;5.42%; n=8) as WT channels (76.87&#b1;6.80%; n=7). Login to comment 104 ABCC8 p.Glu1323Lys The percent of current for WT and E1323K was (70.31&#b1;8.62%; n=8) and (54.12&#b1;10.71%; n=5), respectively. Login to comment 105 ABCC8 p.Met1394Arg F. Faletra et al. / Gene 516 (2013) 122-125 is expressed at the surface at a low level (16.98&#b1;4.87%) but the presence of the M1394R mutant is nearly obliterated at the cell surface (Fig. 2B). Login to comment 106 ABCC8 p.Glu1323Lys In inside-out patch-clamp electrophysiological recordings, small currents were detected in cells expressing the E1323K mutant (relative to WT; see Figs. Login to comment 107 ABCC8 p.Met1394Arg 3A and B and note the current amplitude scale difference), but no currents were observed in cells expressing the M1394R mutant after more than 10 patches. Login to comment 108 ABCC8 p.Glu1323Lys Moreover, channel responses to the metabolic regulator magnesium adenosine diphosphate (MgADP) (Fig. 3A) and the channel agonist diazoxide (Fig. 3B) were evaluated for the E1323K mutant. Login to comment 109 ABCC8 p.Glu1323Lys The E1323K mutant exhibited similar responses to both MgADP and diazoxide as WT channels in the presence of inhibitory ATP (0.1 mM). Login to comment 114 ABCC8 p.Glu1506Lys Since this trafficking defect it could be possible that most of the KATP channels expressed at the cell surface contain only the E1506K SUR1 mutant. Login to comment 115 ABCC8 p.Glu1506Lys We hypothesize that the combined effect of these two mutations could explain the worst phenotype compared to others with the only p.Glu1506Lys. Login to comment 116 ABCC8 p.Glu1323Lys ABCC8 p.Glu1323Lys ABCC8 p.Met1394Arg In patient 2, who is compound heterozygous for the p.[Glu1323Lys]: [Met1394Arg] mutations, both defects seem to have a recessive inheritance and impair the channel trafficking to the plasma membrane, even though E1323K does have normal gating properties. Login to comment