ABCMdb

ABCC8 p.Phe132Leu

None has been submitted yet.

Publications

PMID: 19151370 [PubMed] Pratt EB et al: "Sulfonylurea receptor 1 mutations that cause opposite insulin secretion defects with chemical chaperone exposure."

No. Sentence Comment

129 The recently identified PNDM-causing SUR1 F132L mutation is an example, so are many Kir6.2 mutations reported earlier (8, 29). Login to comment
155 As a control, we also analyzed the Po of the F132L mutant. Login to comment
156 Consistent with that reported previously (30), the Po of F132L (0.71 Ϯ 0.05) tends to be higher than that of WT (Fig. 4), although the difference did not reach statistical significance. Login to comment
272 If R74W and E128K cause functional uncoupling between TMD0-SUR1 and Kir6.2, one might ask if the mutations also result in reduced physical association between the two subunits. Login to comment
273 Several SUR1-TMD0 mutations have been reported to reduce physical association between TMD0 and Kir6.2 in co-immunoprecipitation experiments, including CHI-causing A116P and V187D mutations and PNDM-causing F132L mutation (10, 30). Login to comment
274 The former two do not affect the gating properties of the channel (13), whereas the F132L mutation reduces ATP sensitivity by increasing channel intrinsic Po (30). Login to comment
287 In this regard, it is important to note that we have found the neonatal diabetes-causing mutation F132L also significantly reduces channel expression at the cell surface (57.05 Ϯ 1.75% of WT; n ϭ 3), and that sulfonylureas restore mutant channel surface expression to the same level as WT (109.2 Ϯ 7.05; n ϭ 3). Login to comment
154 As a control, we also analyzed the Po of the F132L mutant. Login to comment
286 In this regard, it is important to note that we have found the neonatal diabetes-causing mutation F132L also significantly reduces channel expression at the cell surface (57.05 afe; 1.75% of WT; n afd; 3), and that sulfonylureas restore mutant channel surface expression to the same level as WT (109.2 afe; 7.05; n afd; 3). Login to comment

PMID: 21321069 [PubMed] Pratt EB et al: "N-terminal transmembrane domain of SUR1 controls gating of Kir6.2 by modulating channel sensitivity to PIP2."

No. Sentence Comment

163 (A) Representative traces from inside-out voltage clamp recordings made from COSm6 cells transfected with Kir6.2C36 (denoted as Kir6.2C) alone or with WT, E128K, or F132L fTMD0 to form mini-KATP channels. Login to comment
172 Again, the F132L mini-channels were included as a control because they have increased Po and decreased ATP sensitivity compared with WT mini-KATP channels (Proks et al., 2007). Login to comment
173 As predicted, the E128K mini-channels were inhibited to a similar extent as Kir6.2C36 channels (85%), whereas the WT and F132L mini-channels were inhibited by only 52 and 15%, respectively (compare Fig. 4, B and C). Login to comment
181 Mini-KATP channels with the F132L mutation were used as a positive control; F132L was identified in patients with severe neonatal diabetes and has been shown to increase intrinsic Po in full-length and mini-KATP channels (Proks et al., 2006, 2007). Login to comment
186 WT, E128K, or F132L Figure 5. E128K full-length KATP channels have decreased PIP2 response. Login to comment
391 Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome. Login to comment

PMID: 17635943 [PubMed] Suzuki S et al: "Molecular basis of neonatal diabetes in Japanese patients."

No. Sentence Comment

161 The reported mutations F132L (4) and H1023Y (5) are located in TMD0 and TMD2, respectively, and functional studies confirmed that these mutations reduced ATP sensitivity. Login to comment

PMID: 17919176 [PubMed] Patch AM et al: "Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period."

No. Sentence Comment

85 Five residues are sites for different amino acid substitutions: V86A/G, F132L/V, D212I/N, R1183Q/W and R1380C/H/L. Login to comment
86 Nine mutations were observed in more than one proband; R1183W (c.3547C>T) was identified in five probands, R1380C (c.4138C>T) in three probands and the remainder; F132L (c.394T>C), D209E (c.627C>A), T229I (c.686C>T), L582V (c.1744C>G), R826W (c.2476C>T), R1183Q (c.3548G>A) and R1380L (c.4139G>T) were each observed in two probands. Login to comment
161 Affected probands and family members can be separated into three distinct groups based T229I/T229I ABCC8 mutations Transient Neonatal Diabetes Mellitus Recessive homozygous mutations R826W (2) H1024Y R1183Q (2) R1183W (5) R1314H R1380C (3) R1380H R1380L (2) D209E D212I D212N R306H V324M C435R L451P L582V (2) Dominant heterozygous mutations Permanent Neonatal Diabetes Mellitus E382K/E382K A1185E/A1185E Mosaic N72S Recessive homozygous or mosaic mutations P45L/G1401R E208K/Y263D T229I/V1523L L438F/M1290V P207S/c.536del4 E1327K+V1523A/ c.1327ins10 Recessive compound heterozygous mutations 1K Dominant heterozygous mutations D209E Q21 L213R L225P(2) I1425V V86A V86G F132L (2) F132V L135P Fig. 2 A diagram illustrating the inheritance of ABCC8 mutations in probands with permanent and transient forms of neonatal diabetes. Login to comment
163 Permanent Neonatal Diabetes Mellitus Transient Neonatal Diabetes Mellitus 1 5 10 15 20 25 30 35 39 N72S V86A V86G F132L F132V L135PP45L P207S E208K D209E Q211K L213R L225P T229I Y263D D209E D212I D212N T229I R306H V324M L438F L451P E382K R826W R1183W R1183Q A1185E E1327K R1314H M1290V R1380C R1380H R1380L G1401R V1523A V1523L H1024YC435R L582V I1425V Fig. 3 The location of missense mutations causing neonatal diabetes within the coding sequence of ABCC8. Login to comment
171 The patient with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and the F132L mutation was not able to discontinue insulin [17]. Login to comment
175 A second patient with the same mutation (F132L) had developmental delay but no epilepsy. Login to comment
176 No neurological features were reported in R1183W/Q A1185E E1327K G1401R V1523A/L NBD1 NBD2 outside membrane inside P45L N72S F132L/V L135P P207S E208K D209E Q211K D212I/N L213R L225P T229I Y263D E382K V86A/G L438F C435R R1380C/H/L L451P R826W TMD0 TMD1 TMD2 R306H V324M L582V H1024Y I1425V R1314H M1290V Fig. 4 A schematic of the membrane topologies of SUR1 showing the location of the ABCC8 missense mutations causing neonatal diabetes. Login to comment
197 Genotype-phenotype Correlation Most of the dominantly acting mutations located in exons 2-5 of the ABCC8 gene (V86A/G, F132L/V, L135P, D209E, Q211K, L213R and L225P) cause PNDM. Login to comment
224 Furthermore, different mutations at the same residue (V86A/G, F132L/V, D212I/N, R1183Q/W and R1380C/H/L) cause either PNDM (V86 and F132) or biphasic TNDM (D212, R1183 and R1380), suggesting a different pathological mechanism. Login to comment
227 The cluster of neonatal diabetes causing mutations in the first five exons of the ABCC8 gene that encode these regions might cause diabetes by increasing the open stability of the channel through interaction with the Kir6.2 subunit as demonstrated for the F132L mutation [17]. Login to comment
247 Functional data have only been published for 8/39 ABCC8 missense mutations to date (F132L [16]; I1425V and H1024Y [13]; mutations (P207S, T229I, A1185E and V1523L [14]; L225P [16]). Login to comment

PMID: 19933268 [PubMed] Hosy E et al: "Impact of disease-causing SUR1 mutations on the KATP channel subunit interface probed with a rhodamine protection assay."

No. Sentence Comment

4 The activating mutation F132L in SUR1, which causes neonatal diabetes, also rendered the channel resistant to Rho block, suggesting that it stabilized an activated conformation by uncoupling TMD0 from the rest of SUR1. Login to comment
98 These observations suggest that activation by distinct pathways converges toward the same Rho phenotype, which we have shown to reflect a particular conformation of the SUR/Kir6.2 interface. The Mutation F132L in SUR1 Induces a Rho-resistant Phenotype- The mutation F132L in TMD0 of SUR1 is responsible for neonatal diabetes (15). Login to comment
109 In the same study, the F132L mutation was shown by co-immunoprecipitation to diminish FIGURE 1. Login to comment
118 It remains that, when probed with the Rho protection assay, the F132L mutation had distinct effects on full-length SUR1 and on the isolated TMD0 domain. Login to comment
121 In conclusion, the mutation F132L in SUR1 produces a Rho-resistant phenotype like the activators MgADP, zinc, or SR47063. Login to comment
123 This suggests that the mutation F132L mimics the presence of openers and causes channel hyperactivity by inducing a conformational change that alters the TMD0/Kir6.2 interface. The Mutation E126A in SUR2A Induces a Rho-sensitive Phenotype-Residue Phe132 is located in the predicted second intracellular loop of SUR1 (24). Login to comment
124 Another residue of this short loop, Glu128 , also causes disease when mutated; mutation E128K is responsible for hyperinsulinism because it reduces KATP channel activity by interfering with proper trafficking of channels to the plasma membrane (16). Login to comment
125 Because of the opposite pathological consequences of F132L and E128K mutations despite their proximity, it was interesting to also subject E128K to the Rho protection assay. Login to comment
133 As for the F132L mutation, we attempted to test the effect of the mutation E126A on TMD0 of SUR2A alone but were unable to record sufficient channel activity from oocytes co-expressing TMD0E126AϩKir6.2⌬C36, thus precluding any valid characterization. Login to comment
173 The neonatal diabetes F132L mutation in SUR1 leads to a constitutive Rho-insensitive conformation, similar to that of the TMD0 ؉ Kir6.2 channel. Login to comment
174 A and B, currents recorded in inside-out patches from Xenopus oocytes co-expressing Kir6.2 and either wild-type SUR1 (A) or the F132L mutant (B). Login to comment
183 Structural Perturbations Induced by Disease-causing Mutations in the Second Intracellular Loop-Mutations F132L and E128K in short intracellular loop 2 located in TMD0 of SUR1 have opposite consequences. Login to comment
184 The neonatal diabetes F132L mutation reduces ATP sensitivity by augmenting open probability (23). Login to comment
186 The hyperinsulinism E128K mutation disrupts channel trafficking and reduces channel function through poor surface expression (16). Login to comment
187 After rescue to the cell surface by a chemical chaperone, the E128K mutant channels are hyperactive with a lower than normal ATP sensitivity like the F132L mutants, although they exhibit an abnormally low Po (25). Login to comment
188 The F132L and E128K mutations cause therefore an abnormally high activity through different mechanisms. Login to comment
189 Pratt et al. (25) speculated that E128K caused functional uncoupling between SUR1 and Kir6.2, thus removing the hypersensitization to ATP brought about by SUR1 (18). Login to comment
190 Based on co-immunoprecipitation of TMD0 alone and Kir6.2 showing that F132L impaired the association of TMD0 and Kir6.2, Proks et al. (23) assumed that TMD0 and SUR behaved identically and concluded that this mutation disconnects SUR from Kir6.2. Login to comment
214 This suggests that although the F132L and E126A mutations lock the TMD0-Kir6.2 interface in distinct conformations where the Rho-binding site is either always masked or always accessible, other regions of SUR are unaffected and can interact with Kir6.2 to modulate its gating. Login to comment
216 Rho Protection Assay Unveils the Mechanism of Disease-causing Mutations-Even though the F132L and E128K mutations in SUR1 both tend to reduce channel sensitivity to ATP, their mechanisms of action obviously differ because F132L increases Po, and E128K decreases Po. Login to comment
217 Nonetheless, after detailed investigation, Proks et al. (23) working on F132L and Pratt et al. (25) working on E128K reached identical conclusions: the mutation disrupts the coupling/interaction between TMD0 and Kir6.2. Login to comment
218 The additional insight obtained by the Rho protection assay appears to resolve this discrepancy as it strengthens the proposed mechanism for E128K while questioning that for F132L. Login to comment
225 This suggests that the conformation of TMD0 in all these cases: F132L, TMD0 alone, and activators, could be similar. Login to comment
226 Thus, the channel hyperactivity caused by the F132L mutation would reflect the stabilization of TMD0 in the same activated conformation that is triggered by activators. Login to comment
100 These observations suggest that activation by distinct pathways converges toward the same Rho phenotype, which we have shown to reflect a particular conformation of the SUR/Kir6.2 interface. The Mutation F132L in SUR1 Induces a Rho-resistant Phenotype- The mutation F132L in TMD0 of SUR1 is responsible for neonatal diabetes (15). Login to comment
111 In the same study, the F132L mutation was shown by co-immunoprecipitation to diminish FIGURE 1. Login to comment
120 It remains that, when probed with the Rho protection assay, the F132L mutation had distinct effects on full-length SUR1 and on the isolated TMD0 domain. Login to comment
126 Another residue of this short loop, Glu128 , also causes disease when mutated; mutation E128K is responsible for hyperinsulinism because it reduces KATP channel activity by interfering with proper trafficking of channels to the plasma membrane (16). Login to comment
127 Because of the opposite pathological consequences of F132L and E128K mutations despite their proximity, it was interesting to also subject E128K to the Rho protection assay. Login to comment
135 As for the F132L mutation, we attempted to test the effect of the mutation E126A on TMD0 of SUR2A alone but were unable to record sufficient channel activity from oocytes co-expressing TMD0E126Aaf9;Kir6.2èc;C36, thus precluding any valid characterization. Login to comment
175 The neonatal diabetes F132L mutation in SUR1 leads to a constitutive Rho-insensitive conformation, similar to that of the TMD0 &#2d19; Kir6.2 channel. Login to comment
176 A and B, currents recorded in inside-out patches from Xenopus oocytes co-expressing Kir6.2 and either wild-type SUR1 (A) or the F132L mutant (B). Login to comment
185 Structural Perturbations Induced by Disease-causing Mutations in the Second Intracellular Loop-Mutations F132L and E128K in short intracellular loop 2 located in TMD0 of SUR1 have opposite consequences. Login to comment
191 Pratt et al. (25) speculated that E128K caused functional uncoupling between SUR1 and Kir6.2, thus removing the hypersensitization to ATP brought about by SUR1 (18). Login to comment
192 Based on co-immunoprecipitation of TMD0 alone and Kir6.2 showing that F132L impaired the association of TMD0 and Kir6.2, Proks et al. (23) assumed that TMD0 and SUR behaved identically and concluded that this mutation disconnects SUR from Kir6.2. Login to comment
219 Nonetheless, after detailed investigation, Proks et al. (23) working on F132L and Pratt et al. (25) working on E128K reached identical conclusions: the mutation disrupts the coupling/interaction between TMD0 and Kir6.2. Login to comment
220 The additional insight obtained by the Rho protection assay appears to resolve this discrepancy as it strengthens the proposed mechanism for E128K while questioning that for F132L. Login to comment
227 This suggests that the conformation of TMD0 in all these cases: F132L, TMD0 alone, and activators, could be similar. Login to comment
228 Thus, the channel hyperactivity caused by the F132L mutation would reflect the stabilization of TMD0 in the same activated conformation that is triggered by activators. Login to comment
99 These observations suggest that activation by distinct pathways converges toward the same Rho phenotype, which we have shown to reflect a particular conformation of the SUR/Kir6.2 interface. The Mutation F132L in SUR1 Induces a Rho-resistant Phenotype- The mutation F132L in TMD0 of SUR1 is responsible for neonatal diabetes (15). Login to comment
110 In the same study, the F132L mutation was shown by co-immunoprecipitation to diminish FIGURE 1. Login to comment
119 It remains that, when probed with the Rho protection assay, the F132L mutation had distinct effects on full-length SUR1 and on the isolated TMD0 domain. Login to comment
122 In conclusion, the mutation F132L in SUR1 produces a Rho-resistant phenotype like the activators MgADP, zinc, or SR47063. Login to comment
134 As for the F132L mutation, we attempted to test the effect of the mutation E126A on TMD0 of SUR2A alone but were unable to record sufficient channel activity from oocytes co-expressing TMD0E126Aaf9;Kir6.2èc;C36, thus precluding any valid characterization. Login to comment
215 This suggests that although the F132L and E126A mutations lock the TMD0-Kir6.2 interface in distinct conformations where the Rho-binding site is either always masked or always accessible, other regions of SUR are unaffected and can interact with Kir6.2 to modulate its gating. Login to comment

PMID: 20922570 [PubMed] Edghill EL et al: "Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11."

No. Sentence Comment

57 For example the R50Q KCNJ11 mutation and the F132V ABCC8 mutation cause isolated diabetes whilst the R50P and F132L mutations cause DEND syndrome [22, 27, 40]. Login to comment
85 One of the most notable R1183W/Q A1185E E1327K G1401R V1523A/L V1524M R1531A NBD1 NBD2 outside membrane inside P45L N72S F132L/V L135P P207S E208K D209E Q211K D212I/N L213R L225P T229I Y263D A269D/N E382K V86A/G R1380C/H/L C435R L438F M1290V L451P R826W R1314H TMD0 TMD1 TMD2 R306H V324M L582V H1024Y I1425V A90V Y356C R521Q N1123D R1153G T1043TfsX74 Fig. 3 Schematic representation of 50 ABCC8 mutations which cause neonatal diabetes. Login to comment

PMID: 18990670 [PubMed] Aittoniemi J et al: "Review. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator."

No. Sentence Comment

98 Co-immunoprecipitation (but not necessarily surface trafficking) is abolished by mutation of F132L in CL2 (Proks et al. 2006a) and of Y195E at the start of CL3 (figure 2). Login to comment
102 For example, the F132L mutation in SUR1 disrupts the physical binding of Kir6.2 and TMD0 (Proks et al. 2007). Login to comment
104 This indicates that the F132L mutation must disrupt an inhibitory interaction between Kir6.2 and TMD0, leaving a stimulatory interaction intact. Login to comment
169 Only one mutation (F132L) has been shown to act this way to date (Proks et al. 2006a, 2007). Login to comment
171 The F132L mutation increases the duration of the bursts of the KATP channel openings and reduces the frequency and duration of the interburst closed states. Login to comment
185 Such naturally occurring mutations TNDM PNDM DEND TNDM PNDM DEND iDEND WT P206L D212N P45L N72S P207S E208K+Y263D D212I T229I A1185E V1522L+Y229I F132L 0 0.05 0.10 0.15 fractionofcurrentremaining in3mMMgATP(a) (b) (i) (ii) Figure 4. Login to comment
204 (a) (b) P45L N72S F132L NH2 A90V V86G COOHL135P exoplasmic cytoplasmic Walker A Walker A linker Walker B linker Walker B V324M E382K C435R L438F L582V R826W H1023Y N1122D R1183Q A1185E R1314H E1327K R1380 L I1425V V1524 L P207S E208K Q211K D212I/N L225P T229I Y263D A269D R306H D209E L213R TMD0 TMD1 TMD2 NBD1 NBD2 CL3 linker site 1 site 2 NBD1 NBD2 R826W R1380 L E1327K I1425V V1524 L Figure 5. Login to comment
97 Co-immunoprecipitation (but not necessarily surface trafficking) is abolished by mutation of F132L in CL2 (Proks et al. 2006a) and of Y195E at the start of CL3 (figure 2). Login to comment
101 For example, the F132L mutation in SUR1 disrupts the physical binding of Kir6.2 and TMD0 (Proks et al. 2007). Login to comment
103 This indicates that the F132L mutation must disrupt an inhibitory interaction between Kir6.2 and TMD0, leaving a stimulatory interaction intact. Login to comment
172 Only one mutation (F132L) has been shown to act this way to date (Proks et al. 2006a, 2007). Login to comment
174 The F132L mutation increases the duration of the bursts of the KATP channel openings and reduces the frequency and duration of the interburst closed states. Login to comment
188 Such naturally occurring mutations TNDM PNDM DEND TNDM PNDM DEND iDEND WT P206L D212N P45L N72S P207S E208K+Y263D D212I T229I A1185E V1522L+Y229I F132L 0 0.05 0.10 0.15 fraction of current remaining in 3 mM MgATP (a) (b) (i) (ii) Figure 4. Login to comment
207 (a) (b) P45L N72S F132L NH2 A90V V86G COOH L135P exoplasmic cytoplasmic Walker A Walker A linker Walker B linker Walker B V324M E382K C435R L438F L582V R826W H1023Y N1122D R1183Q A1185E R1314H E1327K R1380 L I1425V V1524 L P207S E208K Q211K D212I/N L225P T229I Y263D A269D R306H D209E L213R TMD0 TMD1 TMD2 NBD1 NBD2 CL3 linker site 1 site 2 NBD1 NBD2 R826W R1380 L E1327K I1425V V1524 L Figure 5. Login to comment

PMID: 16613899 [PubMed] Proks P et al: "A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes."

No. Sentence Comment

4 We identified a novel heterozygous mutation, F132L, in the ABCC8 gene of a patient with severe developmental delay, epilepsy and neonatal diabetes (DEND syndrome). Login to comment
7 Functional studies of recombinant KATP channels demonstrated that F132L markedly reduces the sensitivity of the KATP channel to inhibition by MgATP and this increases the whole-cell KATP current. Login to comment
55 One patient (ISPAD68) was heterozygous for a novel mutation (F132L) in the ABCC8 gene encoding SUR1. Login to comment
58 The novel F132L mutation results in the substitution of leucine for phenylalanine at residue 132 (p.Phe132Leu) in exon 3 of the ABCC8 gene (c.394T.C; Fig. 1A). Login to comment
60 The F132L mutation was not found in 150 normal chromosomes. Login to comment
66 The region on either side of F132L is also highly conserved (Fig. 1B). Login to comment
68 Clinical characteristics of patient with F132L SUR1 mutation ISPAD68 was a boy born in 1978 with a birth weight of 2200 g to a 29-year-old mother who had previously given birth to two healthy older children. Login to comment
74 F132L mutation, conservation of F132 across species and location of F132L in SUR1. Login to comment
75 (A) Sequencing of ISPAD68 showing a heterozygous mutation (c.394T.C) resulting in the substitution of phenylalanine (TTC) by leucine (CTC) at residue 132 (F132L) of the ABCC8 gene (arrow). Login to comment
81 (C) Schematic of the proposed membrane topologies of SUR1 and Kir6.2 showing the location of F132L (arrowed) in SUR1. Login to comment
104 SUR1 mutant KATP channels are not closed by resting ATP levels To analyse the functional effects of the SUR1-F132L mutation, we studied recombinant KATP channels expressed in Xenopus oocytes. Login to comment
107 In contrast, significant whole-cell Kþ currents were present in the absence of metabolic inhibition (resting currents) in oocytes expressing either homomeric or heterozygous SUR1-F132L mutant channels (Fig. 2). Login to comment
112 SUR1-F132L KATP channels have reduced ATP sensitivity To explore the molecular basis of the reduced metabolic sensitivity of mutant KATP channels, we tested the ability of ATP to block wild-type and mutant channels in inside-out patches. Login to comment
115 (A) Whole-cell currents recorded from Xenopus oocytes coexpressing Kir6.2 and either SUR1 (WT) or SUR1-F132L (homF132L) or both SUR1 and SUR1-F132L (hetF132L) in response to voltage steps of +20 mV from a holding potential of 210 mV. Login to comment
126 These results indicate that the F132L mutation in SUR1 markedly reduces the ability of ATP to inhibit the KATP channel. Login to comment
127 DISCUSSION We report a novel heterozygous mutation, F132L, in the ABCC8 gene encoding SUR1 in a patient with DEND syndrome. Login to comment
130 Genetic evidence for the pathogenicity of the F132L mutation is strong; it is a spontaneous mutation, absent from 150 normal chromosomes and affects a residue that shows evolutionary conservation across species. Login to comment
131 Functional studies also support the pathogenicity of the F132L mutation by revealing that the mutation dramatically reduces the inhibitory potency of MgATP. Login to comment
139 Our results suggest that this physical interaction may be mediated, in part, via the second cytosolic loop of SUR1 and that the F132L mutation influences the interaction of SUR1 with Kir6.2. Login to comment
143 (A) KATP currents recorded in inside-out patches excised from oocytes coexpressing Kir6.2 and either SUR1 or SUR1-F132L (Kir6.2/SUR1-homF132L) or both SUR1 and SUR1-F132L (Kir6.2/SUR1-hetF132L). Login to comment
147 (B) Mean relationship between [ATP] and KATP conductance (G), expressed relative to the conductance in the absence of nucleotide (Gc) for Kir6.2/SUR1 (open circles, n ¼ 6), and heterozygous (solid circles, n ¼ 6) or homomeric (solid squares, n ¼ 7) Kir6.2/SUR1-F132L channels. Login to comment
154 The F132L mutation causes a dramatic decrease in the ability of ATP to inhibit the activity of the KATP channel in both the homozygous and simulated heterozygous states. Login to comment
170 Predicted response to sulphonylurea treatment In the presence of the sulphonylurea tolbutamide (0.5 mmol/l), heterozygous F132L SUR1 channels were blocked by 72%. Login to comment
178 Given the location of residue F132 in TMD0, a region known to regulate KATP channel gating (26,27), it seems reasonable to speculate that the F132L mutation acts by stabilizing the channel open state, thus indirectly reducing its ATP sensitivity. Login to comment
186 Functional analysis demonstrates that the F132L SUR1 mutation acts in a similar way to Kir6.2 mutations causing DEND syndrome by producing a marked reduction in the ability of ATP to block the KATP channel. Login to comment

PMID: 18025408 [PubMed] Rafiq M et al: "Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations."

No. Sentence Comment

54 Doses Table 1-Clinical characteristics of patients with SUR1 mutations according to success of treatment with sulfonylureas Characteristic All patients Patients with successful sulfonylurea treatment Patients with unsuccessful sulfonylurea treatment P* n 27 23 4 Mutation (number of patients) NA V86G†, P45L/G1401R- (2)†, D209E (3)†, T229I/V1523L†, Q211K†, V86A (2)†, E1507G, V215I/V607M, E208K/Y263D†, R1380L (2)‡, D212I (3)§, T229I/T229I‡, R1183W§, L225P†, R826W, and D209N F132L (2)†, F132V†, and N72S† (mosaic). Login to comment
75 Two of these patients with F132V and F132L mutations had increased C-peptide levels following the transfer, but it was decided that the response was insufficient to discontinue insulin. Login to comment
56 Doses Table 1-Clinical characteristics of patients with SUR1 mutations according to success of treatment with sulfonylureas Characteristic All patients Patients with successful sulfonylurea treatment Patients with unsuccessful sulfonylurea treatment P* n 27 23 4 Mutation (number of patients) NA V86Gߤ, P45L/G1401R- (2)ߤ, D209E (3)ߤ, T229I/V1523Lߤ, Q211Kߤ, V86A (2)ߤ, E1507G, V215I/V607M, E208K/Y263Dߤ, R1380L (2)ߥ, D212I (3)&#a7;, T229I/T229Iߥ, R1183W&#a7;, L225Pߤ, R826W, and D209N F132L (2)ߤ, F132Vߤ, and N72Sߤ (mosaic). Login to comment
77 Two of these patients with F132V and F132L mutations had increased C-peptide levels following the transfer, but it was decided that the response was insufficient to discontinue insulin. Login to comment

PMID: 22020219 [PubMed] Babenko AP et al: "Mechanism of KATP hyperactivity and sulfonylurea tolerance due to a diabetogenic mutation in L0 helix of sulfonylurea receptor 1 (ABCC8)."

No. Sentence Comment

14 Consistent with our hypothesis, the diabetogenic F132L in TMD0 of SUR1 increased KATP activity in the absence of nucleotides [15]. Login to comment
93 Consistent with the proposal, F132L in TMD0 and activating mutations in M0 alter intrinsic gating [15,39,40]. Login to comment

PMID: 17584766 [PubMed] Proks P et al: "Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome."

No. Sentence Comment

0 Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome Peter Proks{ , Kenju Shimomura{ , Tim J. Craig, Heidi de Wet, Christophe A.J. Girard and Frances M. Ashcroft* University Laboratory of Physiology, Oxford University, Oxford OX1 3PT, UK Received April 23, 2007; Revised and Accepted June 10, 2007 Activating mutations in the genes encoding the ATP-sensitive potassium (KATP) channel subunits Kir6.2 and SUR1 are a common cause of neonatal diabetes. Login to comment
1 Here, we analyse the molecular mechanism of action of the heterozygous mutation F132L, which lies in the first set of transmembrane helices (TMD0) of SUR1. Login to comment
3 We show that the F132L mutation reduces the ATP sensitivity of KATP channels indirectly, by altering the intrinsic gating of the channel. Login to comment
5 The F132L mutation disrupts the physical interaction between Kir6.2 and TMD0, but does not alter the plasmalemma channel density. Login to comment
33 Recently, we identified the first gain-of-function mutation in SUR1 (F132L) that causes DEND syndrome and showed that it exhibits reduced inhibition by MgATP (17). Login to comment
44 This suggests that mutations in F132L associated with ND may influence the sensitivity of the channel to MgATP indirectly, by altering the single-channel kinetics. Login to comment
47 In this paper, we examine the molecular mechanism by which the F132L mutation in SUR1 influences KATP channel inhibition by ATP. Login to comment
50 RESULTS F132L alters the intrinsic gating of KATP channels The aim of this paper is to determine the molecular mechanism by which the F132L mutation reduces the ATP sensitivity of the KATP channel. Login to comment
52 We first compared the effect of the F132L mutation in SUR1 on the kinetics of single KATP channel currents. Login to comment
55 The F132L mutation dramatically increased the burst duration and reduced the time spent in the interburst intervals. Login to comment
58 The intrinsic open probability (PO) of SUR1-F132L channels was significantly greater (P , 0.05) than that of wild-type channels, being 0.72 + 0.03 (n ¼ 8) for SUR1-F132L, compared with 0.26 + 0.03 (n ¼ 6) for SUR1 channels. Login to comment
59 These differences in channel kinetics suggest that the SUR1-F132L mutation influences KATP channel ATP sensitivity indirectly, via changes in channel gating, as is found for some Kir6.2 mutations. Login to comment
60 Because all patients carrying the F132L mutation are heterozygotes, their pancreatic beta-cells will contain a mixture of wild-type and mutant SUR1. Login to comment
64 Because the channels in the heterozygous population will have different PO, we compared the mean PO of the heterozygous channel population with that of homomeric F132L channels (see Materials and Methods for details). Login to comment
69 Single-channel currents recorded at 260 mV from inside-out membrane patches excised from oocytes expressing Kir6.2/SUR1, Kir6.2/ SUR1-F132L, Kir6.2DC, Kir6.2DC/TMD0 and Kir6.2DC/TMD0-F132L. Login to comment
72 There was a further increase in PO when the F132L mutation was introduced into TMD0 (to 0.82 + 0.02; n ¼ 6). Login to comment
73 These results confirm that the first five transmembrane domains of SUR1 modulate the gating of Kir6.2 (22-24) and show that the F132L mutation enhances this effect. Login to comment
74 Effects of the F132L mutation on the ATP sensitivity of SUR1 channels To explore the effects of the F132L mutation further, we compared the ATP sensitivity of KATP channels composed of Kir6.2 and either wild-type or mutant SUR1. Login to comment
78 The ATP sensitivity of SUR1-F132L mutant channels was further decreased in the presence of 2 mM Mg2+ (Fig. 2B). Login to comment
84 Effects of F132L mutation on the nucleotide activation Because MgATP and MgADP interact with both the NBDs of SUR1, as well as with Kir6.2, it is not easy to separate the stimulatory (via SUR1) and inhibitory (via Kir6.2) effects of these nucleotides. Login to comment
87 A potential problem, however, is that F132L channels have a high intrinsic open probability, which makes it difficult to detect whether Mg-nucleotides cause channel activation. Login to comment
92 Top: KATP currents recorded in response to successive voltage ramps from 2110 to +100 mV in an inside-out patch excised from an oocyte expressing Kir6.2/SUR1 or homKir6.2/ SUR1-F132L channels, as indicated. Login to comment
94 Bottom: (A) Mean relationship between [ATP] and KATP conductance (G), expressed relative to the conductance in the absence of nucleotide (GC) for Kir6.2/ SUR1 (open circle, n = 6), and heterozygous (filled circle, n = 6) or homomeric (filled square, n = 12) Kir6.2/SUR1-F132L channels. Login to comment
98 (B) Mean relationship between [MgATP] and KATP conductance (G), expressed relative to the conductance in the absence of nucleotide (GC) for Kir6.2/SUR1 (open circle, n = 7), and heterozygous (filled circle, n = 7) or homomeric (filled square, n = 10) Kir6.2/SUR1-F132L channels. Login to comment
107 Thus, these data suggest that MgGDP activation may be enhanced by the F132L mutation in SUR1. Login to comment
109 Effects of F132L mutation on the ATP sensitivity of TMD0 channels We next compared the ATP sensitivity of Kir6.2DC/TMD0 channels with heterozygous and homomeric TMD0-F132L channels (Fig. 4). Login to comment
113 The F132L mutation further reduced the ATP sensitivity of Kir6.2DC/TMD0 channels (Fig. 4A): the IC50 for ATP inhibition was 2.1 and 4.2 mM for hetTMD0-F132L and homTMD0-F132L channels, respectively (Table 1). Login to comment
115 This was not only true for wild-type TMD0, but also for hetTMD0-F132L and homTMD0-F132L (Table 1). Login to comment
118 The pedestal was of similar magnitude in both the absence and presence of Mg2+ , being 10% for wild-type channel, 25% for hetTMD0-F132L and 40% for homTMD0-F132L channels at 10 mM ATP. Login to comment
119 The F132L mutation disrupts the interaction between TMD0 and Kir6.2 Our results suggest that the F132L mutation may influence KATP channel gating by altering the interaction between SUR1 and Kir6.2. Login to comment
122 Xenopus oocytes were co-injected with Kir6.2DC-HA and either wild-type TMD0, TMD0-F132L or a mixture of both (to simulate heterozygosity). Login to comment
124 The F132L mutation reduced the binding of TMD0 to Kir6.2 by 90% (P , 0.001), indicating that F132 is crucial for this interaction. Login to comment
125 Heterozygous expression of TMD0-F132L led to an 75% reduction in binding (Fig. 5A), but this was not significantly different from that of homTMD0-F132L (P ¼ 0.28). Login to comment
128 Mean hetKir6.2/SUR1-F132L and homKir6.2/SUR1-F132L currents recorded in the presence of 200 mM ATPgAA and 200 mM ATPgAA+100 mM MgGDP, as indicated. Login to comment
132 Values of IC50 for ATP inhibition of various KATP channels in both Mg2þ -containing and Mg2þ -free solutions Channel IC50 Mg2þ -free 2 mM Mg2þ Kir6.2/SUR1 7 + 1 mM (n ¼ 7) 14 + 1 mM (n ¼ 7) hetKir6.2/SUR1-F132L 30 + 1 mM (n ¼ 7) 122 + 23 mM (n ¼ 8) homKir6.2/SUR1-F132L 51 + 7 mM (n ¼ 8) 910 + 180 mM (n ¼ 10) Kir6.2DC/TMD0 700 + 65 mM (n ¼ 6) 603 + 32 mM (n ¼ 6) hetKir6.2DC/TMD0-F132L 2.10 + 0.16 mM (n ¼ 6) 2.57 + 0.13 mM (n ¼ 6) homKir6.2DC/TMD0-F132L 4.20 + 1.05 mM (n ¼ 6) 6.05 + 0.94 mM (n ¼ 6) A possible explanation for the reduced physical interaction between TMD0 and SUR1 produced by the F132L mutation is that the interaction is state-dependent, occurring only when the channel is in the closed state. Login to comment
139 Thus, we next examined whether the F132L mutation altered surface expression of the KATP channel complex. Login to comment
141 Co-expression with SUR1/TMD0 enhanced surface expression of both Kir6.2 and Kir6.2DC: however, this was unaffected by the F132L mutation (Fig. 6). Login to comment
142 DISCUSSION Molecular mechanism of action Single-channel analysis revealed that the F132L mutation dramatically enhances the burst duration and the intrinsic open probability (PO) of both homomeric Kir6.2/ SUR1-F132L and Kir6.2/TMD0-F132L channels. Login to comment
143 Thus, F132L is a gating mutation that alters the ATP-sensitivity of the KATP channel indirectly, via stabilization of the channel open state (30,34). Login to comment
149 Our results further show that the F132L mutation impairs this physical association. Login to comment
152 Top: KATP currents recorded at 260 mV in an inside-out patch excised from an oocyte expressing Kir6.2DC/TMD0 or homozygous Kir6.2DC/TMD0-F132L channels. Login to comment
154 Bottom: (A) Mean relationship between [ATP] and KATP conductance (G), expressed relative to the conductance in the absence of nucleotide (GC) for Kir6.2DC /TMD0 (open circle, n = 6) and heterozygous (filled circle, n = 6) or homomeric (filled square, n = 6) Kir6.2DC /TMD0-F132L channels. Login to comment
158 (B) Mean relationship between [MgATP] and KATP conductance (G), expressed relative to the conductance in the absence of nucleotide (GC) for Kir6.2DC /TMD0 (open circle, n = 5) and heterozygous (filled circle, n = 7) or homomeric (filled square, n = 10) Kir6.2DC /TMD0-F132L channels. Login to comment
165 Because the F132L mutation markedly affected channel gating, whether in TMD0 or full-length SUR1, the physical association of these two subunits may be required for the modulation of Kir6.2 kinetics by SUR1. Login to comment
169 Because the F132L mutation increases the PO of Kir6.2/TMD0 channels even further, it appears that there may be an additional inhibitory effect of TMD0 that is abolished by mutation of F132. Login to comment
175 Although we cannot rule out an allosteric effect, the fact the F132L mutation greatly reduces the physical interaction between Kir6.2 and TMD0 suggests that the intracellular loop within which F132 lies must be in close proximity to the cytoplasmic domains of Kir6.2. Login to comment
176 Heterozygosity and nucleotide sensitivity Our results demonstrate that both the ATP and MgATP concentration-inhibition curves for heterozygous Kir6.2/ SUR1-F132L channels are intermediate between those of wild-type and homKir6.2/SUR1-F132L channels. Login to comment
178 (A) Co-immunoprecipitation of FLAG-tagged TMD0 and Kir6.2DC, using wild-type or F132L TMD0 and wild-type Kir6.2DC. Login to comment
192 Mg2+ produced a dramatic reduction in the ATP sensitivity of homKir6.2/SUR1-F132L and hetKir6.2/SUR1-F132L channels. Login to comment
195 This suggests that the mechanism by which nucleotide binding/hydrolysis at the NBDs of SUR1 is translated in opening of the Kir6.2 pore is also enhanced by the F132L mutation. Login to comment
204 It is not yet clear if there is an overlap between the ATP sensitivity of the two phenotypes (DEND and I-DEND) and whether additional factors present in patients may further enhance the severity of the syndrome caused by the F132L mutation. Login to comment
248 Co-immunoprecipitation of TMD0 and Kir6.2 Oocytes were injected with 5 ng of Kir6.2DC mRNA and 5 ng of either TMD0, mutant TMD0 (F132L or C166S) or a 50:50 mix of wild-type and mutant TMD0 mRNAs. Login to comment

PMID: 18767144 [PubMed] Flanagan SE et al: "Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism."

No. Sentence Comment

121 Syndromic PNDM A total of 10 activating KCNJ11 mutations (R50P, R50G, Q52R, G53D, V59G, C166F, C166Y, I167L, I296L, and G334D) and one ABCC8 mutation (F132L) have been reported that result in a severe phenotype of development delay, epilepsy, and neonatal diabetes, termed DEND syndrome [Gloyn et al., 2004b, 2006; Flanagan et al., 2006; Proks et al., 2006a; Masia et al., 2007b; Shimomura et al., 2007; Suzuki et al., 2007]. Login to comment

PMID: 19021632 [PubMed] Klupa T et al: "Mutations in the ABCC8 (SUR1 subunit of the K(ATP) channel) gene are associated with a variable clinical phenotype."

No. Sentence Comment

66 The causative relationships between both de novo variants, V86A and F132V, and diabetic phenotype are evident, particularly as different mutations at these residues (F132L and V86G) were previously described in other cases of neonatal diabetes4,18 in addition to another case of PNDM with the V86A mutation.20 The R826W mutation was found in two families in this study but they are not known to share a common ancestor. Login to comment
80 Interestingly, both previously reported carriers of the mutation at this residue, F132L, showed some degree of developmental delay.18 A genotype/phenotype correlation, that includes the clinical picture and the response to the SU, has been reported for both KCNJ11 and ABCC8 mutations,22,23 although the correlation for Kir6Æ2 is strongest. Login to comment

PMID: 17317760 [PubMed] Masia R et al: "A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM)."

No. Sentence Comment

149 Two reports have identified three SUR1 mutations associated with PNDM (F132L, L213R, and I1424V) and five associated with transient neonatal diabetes (11,12). Login to comment
150 Common to F132L and I1424V is an increased sensitivity of the channel to Mg nucleotides, such that channel overactivity results at physiological nucleotide concentrations. Login to comment
151 Our results are consistent with these previous studies, as L225P increases channel sensitivity to Mg nucleotides without altering intrinsic gating or inhibition by ATP. Login to comment
152 The effects of L225P are similar to those of the PNDM-associated I1424V mutation (12) but not as severe as those of the DEND (Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome)-associated F132L mutation (11). Login to comment
153 The effects of L225P are similar to those of the PNDM-associated I1424V mutation (12) but not as severe as those of the DEND (Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome)-associated F132L mutation (11). Login to comment

PMID: 17668386 [PubMed] Ellard S et al: "Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects."

No. Sentence Comment

27 Apparent spontaneous mutations were confirmed by testing parental and proband DNA samples with use of a panel of six microsatellite markers on chromosome 11p15.11 Heterozygous de novo mutations V86A, V86G, F132L, F132V, D209E, Q211K, and L225P were present in eight patients (table 2). Login to comment
73 Details of ABCC8 Mutations and Clinical Information ISPAD Number Mutation (Protein Effect) Nucleotide Change Zygosity Age at Diagnosis (wk) Birth Weighta (Percentile) Neurological Feature Developmental Delay Muscle Weakness Epilepsy 123 V86Ab c.257TrC Heterozygous 8 2,900 (9) No No No 124 V86G c.257TrG Heterozygous 5 2,900 (13) No No No 68 F132Lb c.394TrC Heterozygous 13 2,200 (!1) Yes Yes Yes 125 F132L c.394TrC Heterozygous 26 2,440 (9) Yes Yes No 82 F132V c.394TrG Heterozygous 20 NA No No No 46 D209E c.627CrA Heterozygous 5 2,720 (13) No No No 134 Q211Kb c.631CrA Heterozygous 16 2,400 (3) No No No 122 L225Pc c.674TrC Heterozygous 4 2,500 (11) No No No 117 E382K c.1144GrA Homozygous 8 2,700 (4) No No No 118 A1185E c.3554CrA Homozygous 0 4,200 (95) No Yes Yes 116 N72S c.215ArG Mosaic 5 3,870 (74) No No No 47 P45L ϩ G1401R [c.134CrT] ϩ [c.4201GrA] Compound heterozygous 6 2,520 (18) Yes Yes No 119 E208K ϩ Y263D [c.622GrA] ϩ [c.787TrG] Compound heterozygous 13 2,950 (28) Yes No No 120 T229I ϩ V1523L [c.686CrT] ϩ [c.4567GrT] Compound heterozygous 4 NA No No No 78 P207S ϩ Y179X [c.619CrT] ϩ [c.536_539delATGG] Compound heterozygous 8 3,290 (29) No No No 121 [E1327K; V1523A] ϩ T1043QfsX74 [c.3979GrA; 4568CrT] ϩ [c.3127_3129delACCinsCAGCCAGGACCTG] Compound heterozygous 1 2,380 (!1) No No No a NA p not available. Login to comment
94 To simulate the patient`s genotype, we coinjected Kir6.2 mRNA with hetF132L (1:1 mix of WT and F132L SUR1 mRNAs); homA1185E or P207S (mutant SUR1 only); or V1523LϩT229I (1:1 mix of V1523L and T229I SUR1). Login to comment
102 ForIC p 15 h p 1.11 n p 650 hetSUR1-F132L (a), mM, , and . Login to comment
103 For homSUR1-P207S (b), mM, , and . Login to comment
133 To simulate the heterozygous state (e.g., F132L), Kir6.2 was coexpressed with a 1:1 mixture of wild-type and mutant SUR1 mRNA. Login to comment
95 To simulate the patient`s genotype, we coinjected Kir6.2 mRNA with hetF132L (1:1 mix of WT and F132L SUR1 mRNAs); homA1185E or P207S (mutant SUR1 only); or V1523Laf9;T229I (1:1 mix of V1523L and T229I SUR1). Login to comment
136 To simulate the heterozygous state (e.g., F132L), Kir6.2 was coexpressed with a 1:1 mixture of wild-type and mutant SUR1 mRNA. Login to comment

PMID: 17389331 [PubMed] Vaxillaire M et al: "New ABCC8 mutations in relapsing neonatal diabetes and clinical features."

No. Sentence Comment

78 and in one patient previously reported with a SUR1 mutation (F132L) and severe DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome (21). Login to comment
82 and in one patient previously reported with a SUR1 mutation (F132L) and severe DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome (21). Login to comment

PMID: 20876358 [PubMed] Proks P et al: "Activation of the K(ATP) channel by Mg-nucleotide interaction with SUR1."

No. Sentence Comment

420 Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome. Login to comment
424 Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome. Login to comment

PMID: 21054355 [PubMed] Rubio-Cabezas O et al: "Permanent neonatal diabetes mellitus--the importance of diabetes differential diagnosis in neonates and infants."

No. Sentence Comment

307 Clin Endocrinol (Oxf) 2009;71:358-62. 50 Proks P, Shimomura K, Craig TJ, Girard CA, Ashcroft FM. Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome. Login to comment

PMID: 18450778 [PubMed] Dupuis JP et al: "Three C-terminal residues from the sulphonylurea receptor contribute to the functional coupling between the K(ATP) channel subunits SUR2A and Kir6.2."

No. Sentence Comment

37 However, most of these works concluded that there was a major role of TMD0 in the control of the Kir6.2 open probability (Po) but none of them defined it as essential in pharmacological responsiveness of the channel, except for the report of a heterozygous mutation in cytoplasmic loop 2, F132L, responsible for changes in ATP and tolbutamide sensitivity (Proks et al. 2006). Login to comment

PMID: 26621776 [PubMed] Cooper PE et al: "Differential mechanisms of Cantu syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel."

No. Sentence Comment

232 Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome. Login to comment

PMID: 24399968 [PubMed] Martin GM et al: "Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels."

No. Sentence Comment

348 However, it has been shown that many mutations identified in PNDM (Gloyn et al., 2004; Proks et al., 2004, 2005, 2006; Koster et al., 2005) also reduce channel biogenesis efficiency, including Q52R, V59G/M, R201C/H and I296L in Kir6.2 (Lin et al., 2006a) as well as F132L in SUR1 (Pratt et al., 2009) when expressed heterologously as homomeric mutant channels (Table 2). Login to comment
356 Mutation Surface expression Gating References increased by SU property SUR1 F132L Yes Increased Po Pratt et al., 2009 V324M N.D. Increased MgADP sensitivity Zhou et al., 2010 Kir6.2 C42R N.D. Increased Po Yorifuji et al., 2005 Q52R Yes Increased Po Proks et al., 2004; Lin et al., 2006a V59G Yes Increased Po Proks et al., 2004; Lin et al., 2006a V59M Yes Increased Po Koster et al., 2005; Lin et al., 2006a R201C Yes Decreased ATP inhibition Proks et al., 2004; Lin et al., 2006a R201H Yes Decreased ATP inhibition Proks et al., 2004; Lin et al., 2006a Pro226_ Pro232del N.D. Increased Po Lin et al., 2013 I296L Yes Increased Po Proks et al., 2005; Lin et al., 2006a CONCLUSIONS AND PERSPECTIVES Pharmacological chaperones have emerged as promising therapeutic tools for treating diseases resulting from defective protein folding and/or trafficking. Login to comment