ABCC8 p.Ala30Val

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PMID: 22562119 [PubMed] Lin YW et al: "Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic K(ATP) channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits."
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8 Here, we report a case of diabetes in a 7-mo old child with compound heterozygous mutations in ABCC8 (SUR1[A30V] and SUR1[G296R]).
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ABCC8 p.Ala30Val 22562119:8:107
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12 In addition, the IC50 for ATP inhibition of homomeric A30V channels was increased ~6-fold, and was increased ~3-fold for both heteromeric A30V + WT channels or compound heterozygous (A30V + G296R) channels.
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ABCC8 p.Ala30Val 22562119:12:54
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ABCC8 p.Ala30Val 22562119:12:138
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ABCC8 p.Ala30Val 22562119:12:183
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32 Direct sequencing of his DNA revealed two mutations in the ABCC8 gene c.886 G > A (G296R) and c.89 C > T (A30V), the first of which is maternally derived and the second is paternally derived.
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ABCC8 p.Ala30Val 22562119:32:106
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41 As shown in Figure 1A, neither heteromeric single mutant channels ([A30V + WT], referred to as hetA30V and [G296R + WT], referred to as hetG296R) nor compound heterozygous channels ([A30V + G296R]) exhibited significantly different maximum 86 Rb+ efflux rates in the presence of metabolic inhibitors.
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ABCC8 p.Ala30Val 22562119:41:68
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ABCC8 p.Ala30Val 22562119:41:183
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53 k2,basal /k2,MI calculated from WT, het A30V, het G296R and SUR1[A30V + G296R] are 0.07 &#b1; 0.005, 0.08 &#b1; 0.01, 0.1 &#b1; 0.01 and 0.16 &#b1; 0.01 (n = 4-9).
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ABCC8 p.Ala30Val 22562119:53:40
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ABCC8 p.Ala30Val 22562119:53:65
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56 Homozygous G296R channels exhibit a slightly right-shifted dose-response, but homozygous A30V channels exhibit a marked and significantly right-shifted ATP sensitivity (Fig. 4B).
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ABCC8 p.Ala30Val 22562119:56:89
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57 In the heteromeric case, mimicking the disease condition, hetG296R channels are not markedly different from WT, but hetA30V and compound heterozygous A30V + G296R channels both exhibit a significant rightward shift when compared with WT channels (Fig. 4C).
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ABCC8 p.Ala30Val 22562119:57:150
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64 A30V and G296R mutants are located at the TMD0 and the cytosolic linker region (L0) of SUR1 3 (Fig. 2).
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ABCC8 p.Ala30Val 22562119:64:0
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66 Here we characterized the sensitivity to MgADP activation, as well as inhibitory ATP sensitivity (without Mg2+ ), of homomeric A30V channels (labeled as homA30V), homomeric G296R channels (labeled as homG296R), hetA30V, hetG296R and compound heterozygous channels [A30V + G296R].8,18,19 Representative recordings of channel response to MgADP from WT and compound heterozygous mutants are shown in Figure 3A and summary results are shown in Figure 3B.
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ABCC8 p.Ala30Val 22562119:66:127
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ABCC8 p.Ala30Val 22562119:66:265
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67 Homomeric G296R channels exhibit dramatically increased MgADP activity, while homomeric A30V channels show no significant enhancement (Fig. 3B).
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ABCC8 p.Ala30Val 22562119:67:88
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69 On the other hand, it is noticeable that A30V homomeric channels show significant increased current in 0.1 mM MgATP, reflecting an additive consequence of the two distinct mutant effects (Fig. 3B).
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ABCC8 p.Ala30Val 22562119:69:41
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71 Given that homomeric A30V channels showed greatly reduced ATP sensitivity in 0.1 mM ATP (with 0.5 mM free Mg2+ ), we characterized the sensitivity to inhibitory ATP, without any confounding effects of Mg-nucleotides.
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ABCC8 p.Ala30Val 22562119:71:21
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74 Membrane topology of SUR1 and the predicted locations of A30V and 296R.
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ABCC8 p.Ala30Val 22562119:74:57
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75 The red filled circles indicate the predicted positions for A30V at the N terminus of its 1st transmembrane domain (TMD0) and G296R at the L0 linker region before TMD1 domain.
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ABCC8 p.Ala30Val 22562119:75:60
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79 Representative inside-out patch clamp recordings of WT and A30V + G296R in different MgATP and MgADP concentrations (A).
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ABCC8 p.Ala30Val 22562119:79:59
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81 (B) Relative channel currents in 0.1 mM MgATP and plus 0.5 mM MgADP for WT, homA30V, homG296R, hetA30V, hetG296R and compound heterozygous [A30V + G296R] channels as indicated.
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ABCC8 p.Ala30Val 22562119:81:140
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92 (A) Representative currents recorded by inside-out excised patch-clamp technique from COSm6 cells expressing WT, homA30V, homG296R and [A30V + G296R] at +50 mV pipette potential. Patches were exposed to different concentrations of Mg-free ATP as indicated.
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ABCC8 p.Ala30Val 22562119:92:136
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96 Fitted K1/2 for WT, homA30V and homG296R channels are 9.65, 53.31 and 28.11 (in bc;M) and the Hill coefficients are 1.22, 1.04 and 1.19, respectively. (C) The fitted K1/2 for WT, hetA30V, hetG296R and [A30V + G296R] are 9.65, 25.75, 12.75 and 25.45 (in bc;M) and the Hill coefficients are 1.22, 1.28, 1.29 and 1.23, respectively. from the child and both parents.
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ABCC8 p.Ala30Val 22562119:96:205
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98 Two mutations were found in ABCC8 in the proband: c.886 G > A, predicted to cause a G296R amino acid change, was maternally transmitted, and c.89 C > T, predicted to cause A30V amino acid change, was paternally transmitted.
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ABCC8 p.Ala30Val 22562119:98:172
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125 (A) Representative currents recorded by inside-out excised patch-clamp technique from COSm6 cells expressing WT and [A30V + G296R] at +50 mV pipette potential. Patches were exposed to different concentrations of glibenclamide as indicated (free Mg-nucleotide).
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ABCC8 p.Ala30Val 22562119:125:117
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