ABCMdb

ABCC6 p.Gly1302Arg

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Publications

PMID: 14965249 [PubMed] Haimeur A et al: "The MRP-related and BCRP/ABCG2 multidrug resistance proteins: biology, substrate specificity and regulation."

No. Sentence Comment

555 Three missense NBD2 MRP6 mutants (Val1298Phe, Gly1302Arg and Gly1321Ser) found in PXE patients were recently shown by in vitro studies to exhibit normal levels of MgATP binding although transport of GSH conjugated organic anion substrates, including LTC4, wasnot detectable [352]. Login to comment

PMID: 16006996 [PubMed] Conseil G et al: "Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters."

No. Sentence Comment

56 In the kidney, glomeruli and distal collecting tubules express MRP1, and, in the brain, MRP1 appears to form part of the drug permeability barrier Fig. 1 CF (CFTR/ABCC7) Q1291R E1228G Q1238R G1244E/V G1247R G1249R S1251N S1255P/L W1282G/R/C R1283K/M N1303K Y1307C E1321Q K1351E Q1352H R1268Q V1298F T1301I G1302R A1303P R1314W/Q G1321S R1339C Q1347H I1350L G1354R D1361N Q1382R A1450T R1347E R1351P V1359G/M S1368A G1377R G1382S R1392H R1419C R1435Q G1477R G1479R R1492W E1505K DJS (MRP2/ABCC2) NBD1 NBD2 COOH MEMBRANE MSD MSD MSD 12131415161710116 7 8 91 23 4 5TM H2 N Extracellular Intracellular PXE (ABCC6) PHHI (SUR1/ABCC8) Two-dimensional structure of MRP-related proteins. Login to comment

PMID: 11536079 [PubMed] Le Saux O et al: "A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum."

No. Sentence Comment

85 PXE Mutations The most-prevalent mutations detected in the ABCC6 gene were missense substitutions (21 [58.3%] mutations, Table 1 ABCC6 Mutations in a Cohort of Patients with PXE CHANGE IN STATUS a ORIGIN(S)b EXON(S)c REFERENCE(S)Amino Acid Nucleotide … 179-195del ht Belgium 2 Present study … 938-939insT ch, ht SA, UK 8 Present study N411K 1233TrG ht US 10 Present study A455P 1363GrC Nd Nd 11 Uitto et al. (2001) R518Q 1553GrA ch, ht Belgium 12 Present study, Uitto et al. (2001) F568S 1703TrC ch US 13 Present study … ABCC6del15 hm SA 15 Present study … 1944del22 ht Holland 16 Bergen et al. (2000) … 1995delG ht Germany 16 Present study L673P 2018TrC ch SA 16 Present study R765Q 2294GrA ht Germany 18 Present study Y768X 2304CrA ch, ht SA 18 Present study … 2322delC ht US 18 Present study … 2542delG Nd Nd 19 Uitto et al. (2001) … IVS21ϩ1GrT ch US, Germany i-21 Present study, Uitto et al. (2001) R1030X 3088CrT ht SA, UK 23 Present study R1114P 3341GrC hm UK 24 Present study S1121W 3362CrG ch Germany 24 Present study R1138W 3412CrT hm Nd 24 Ringpfeil et al. (2000) R1138P 3413GrC ch Germany 24 Present study R1138Q 3413GrA ch UK, US 24 Present study, Ringpfeil et al. (2000) R1141X 3421CrT All All 24 Present study and othersd R1164X 3490CrT ch Germany, UK 24 Ringpfeil et al. (2001) G1203D 3608GrA ch Germany 25 Present study … IVS26-1GrA ch Belgium i-26 Present study, Ringpfeil et al. (2000, 2001) Q1237X 3709CrT ch Belgium 26 Present study … 3775delT ht, hm SA, US, Holland 27 Present study, Bergen et al. (2000) V1298F 3892GrT ht US 28 Present study T1301I 3902CrT ch Belgium 28 Present study G1302R 3904GrA hm US 28 Present study A1303P 3907GrC ch Belgium 28 Present study R1314W 3940CrT hm US 28 Present study R1314Q 3941GrA ch Germany 28 Present study G1321S 3961GrA ht US 28 Present study R1339C 4015CrT All SA, US 28 Present study, Struk et al. (2000) Q1347H 4041GrC hm US 28 Present study D1361N 4081GrA ch Germany 29 Present study … 4104delC ch Belgium 29 Present study R1398X 4192CrT ch Belgium 29 Present study … ABCC6del23-29 ch US 23-29 Present study, Ringpfeil et al. (2001) … 4220insAGAA ht Holland 30 Bergen et al. (2000) I1424T 4271TrC ht US 30 Present study … ABCC6del ht Holland all Bergen et al. (2000) a Nd p not determined; hm p homozygote; ht p heterozygote; ch p compound heterozygote. Login to comment
94 Although most of the mutations reported here appear to be unique, a few disease-causing variants have been found to occur frequently in apparently unrelated individuals; R1141X was found at Table 2 Frequencies of Mutant Alleles Found in a Cohort of 101 Unrelated Patients with PXE MUTATION a OVERALL EUROPE UNITED STATES No. of Alleles Frequency (%) No. of Alleles Frequency (%) No. of Alleles Frequency (%) R1141X 38 18.8 33 28.4 3 4.1 ABCC6del23-29 26 12.9 5 4.3 21 28.4 IVS21ϩ1GrT 7 3.5 4 3.4 3 4.1 G1302R 4 2.0 0 .0 4 5.4 A1303P 4 2.0 3 2.6 1 1.4 R1314W 3 1.5 0 .0 3 4.1 R518Q* 3 1.5 1 .9 1 1.4 3775delT* 3 1.5 2 1.7 0 .0 R1138Q 2 1.0 1 .9 1 1.4 V1298F 2 1.0 0 .0 2 2.7 R1339C 2 1.0 0 .0 2 2.7 Q1347H 2 1.0 0 .0 2 2.7 4104delC* 2 1.0 1 .9 0 .0 179-195del 1 .5 1 .9 0 .0 938-939insT* 1 .5 0 .0 0 .0 N411K 1 .5 0 .0 1 1.4 F568S 1 .5 0 .0 1 1.4 1995delG 1 .5 1 .9 0 .0 R765Q 1 .5 1 .9 0 .0 2322delC 1 .5 0 .0 1 1.4 R1030X* 1 .5 0 .0 0 .0 R1114P 1 .5 1 .9 0 .0 S1121W 1 .5 1 .9 0 .0 R1138P 1 .5 1 .9 0 .0 G1203D 1 .5 1 .9 0 .0 IVS26-1GrA 1 .5 1 .9 0 .0 Q1237X 1 .5 1 .9 0 .0 W1241C 1 .5 1 .9 0 .0 T1301I 1 .5 1 .9 0 .0 R1314Q 1 .5 1 .9 0 .0 D1361N 1 .5 1 .9 0 .0 R1398X 1 .5 1 .9 0 .0 G1321S 1 .5 0 .0 1 1.4 I1424T 1 .5 0 .0 1 1.4 ? Login to comment

PMID: 11880368 [PubMed] Ilias A et al: "Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6)."

No. Sentence Comment

47 To study the effect of PXE mutations on MRP6/ABCC6 function, we have inserted three naturally occurring PXE mutations, V1298F, G1302R, and G1321S (20), into our cDNA by using inverse PCR mutagenesis (21). Login to comment
48 One of the missense mutations (G1302R) we studied was found in homozygous form (20) in two unrelated patients, whereas the other two were detected in heterozygous form. Login to comment
77 Using this cDNA with a verified sequence, we have generated recombinant baculoviruses containing the wild type human ABCC6 cDNA as well as that of three ABCC6 mutant variants (V1298F, G1302R, and G1321S). Login to comment
84 Moreover, as shown by immunostaining in Fig. 1B, all three mutant forms of human ABCC6 (V1298F, G1302R, and G1321S) were expressed in about the same amount as the wild type protein (94, 78, and 88% of the wild type, respectively, as measured by densitometry) and all with the correct molecular mass. Login to comment
157 Transport Studies of Mutants ABCC6 Variants Causing PXE-Based on these results and to analyze the transport activity of the PXE-causing ABCC6 mutations, we studied the NEM-GS and the LTC4 uptake in Sf9 cell membrane vesicles containing three ABCC6 variants, V1298F, G1302R, and G1321S. Login to comment
163 Isolated membranes of Sf9 cells expressing wild type or mutant (V1298F, G1302R, and G1321S) ABCC6 transporters were incubated in the presence of 2 ␮M Mg-8-N3-[␥-32 P]ATP and either orthovanadate (1 mM) or AlF4 (2 mM) was added as a trapping anion. Login to comment
173 Effect of V1298F, G1302R, and G1321S mutations on the transport and nucleotide-trapping activity of human ABCC6. Login to comment
182 The G1302R mutant, however, could form the occluded nucleotide intermediate state, as incorporation of radioactive label was detected under catalytic conditions in this mutant (Fig. 4C). Login to comment
223 In the present study we expressed and investigated three PXE mutants, V1298F, G1302R, and G1321S, that were all within the C-proximal ABC domain (see Fig. 1A). Login to comment
239 Interestingly, nucleotide trapping was performed by the G1302R mutant (Fig. 4C), which suggests that the transport/ ATPase cycle is arrested at a later step in this transport-negative mutant. Login to comment

PMID: 12673275 [PubMed] Hu X et al: "ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum."

No. Sentence Comment

30 of patients Allele 1 Consequence Exon Allele 2 Consequence Exon Mode of inheritance in family 1 2247C>T Q749X 17 s 1 3421C>T R1141X 24 2247C>T Q749X 17 ar 9 3421C>T R1141X 24 ar,s, n 1 3421C>T R1141X 24 1944del22 Frameshift 16 n 3 3421C>T R1141X 24 Deletion A995del405 23-29 ar 1 3421C>T R1141X 24 4182delG Frameshift 29 ar 1 3421C>T R1141X 24 3775delT Frameshift 27 s 3 3421C>T R1141X 24 3421C>T R1141X 24 ar, s 1 2294G>A R765Q 18 3775delT Frameshift 27 ar 1 3341G>A R1114H 24 n 1 3390C>T T1130M 24 3390C>T T1130M 24 ar 1 3663C>T R1221C 26 3775delT Frameshift 27 n 1 3904G>C G1302R 28 s 1 3907G>A A1303P 28 Deletion A995del405 23-29 ar 1 4182G>T K1394N 29 Deletion A995del405 23-29 ar 1 4182delG Frameshift 29 n 1 4182delG Frameshift 29 4182delG Frameshift 29 ar 1 4377C>T R1459C 30 ad?, s,n 2 3775delT Frameshift 27 s,n 1 3775delT Frameshift 27 Deletion all? Login to comment
38 Table 2 Summary of ABCC6/MRP6 mutations associated with PXE known today: our data combined with those of the literature Mutation Protein alteration Nucleotide substitution Location Reference Nonsense Q378X 1132C > T Exon 9 19,20 R518X 1552C > T Exon 2 41 Q749X 2247C > T Exon 17 This study Y768X 2304C > A Exon 18 22 R1030X 3088C > T Exon 23 22 R1141X 3421C > T Exon 24 12,20,22,38,39, this study R1164X 3490C > T Exon 24 12,41 Q1237X 3709C > T Exon 26 22 R1398X 4192C >T Exon 29 22 T364R Missense N411K 1091C > G Exon 9 20 A455P 1233T > G Exon 10 22 R518Q 1363G > C Exon 11 38 F568S 1553G > A Exon 12 22,38 L673P 1703T > C Exon 13 22 R765Q 2018T > C Exon 16 22 R1114P 2294G > A Exon 18 22, this study R1114H 3341G > C Exon 24 22 S1121W 3341G > A Exon 24 This study T1130M 3362C > G Exon 24 22 R1138W 3390C > T Exon 24 This study R1138Q 3412C > T Exon 24 12 R1138P 3413G > A Exon 24 12,22 G1203D 3413G > C Exon 24 22 R1221C 3608G > A Exon 25 22 V1298F 3663C > T Exon 26 This study T1301I 3892G > T Exon 28 22 G1302R 3902C > T Exon 28 22 A1303P 3904G > A Exon 28 22, this study R1314W 3907G > C Exon 28 22, this study R1314Q 3940C > T Exon 28 22 G1321S 3941G > A Exon 28 22 R1339C 3961G > A Exon 28 22 Q1347H 4015C > T Exon 28 22,39 G1354R 4041G > C Exon 28 22 D1361N 4060G > C Exon 29 20,38 K1394N 4081G > A Exon 29 22 I1424T 4182G > T Exon 29 This study R1459C 4271T > C Exon 30 22 4377C > T Exon 30 This study Frameshift IVS17-12delT T Intron 17 This study IVS21+1G>T Intron 21 22,38 IVS26-1G>A Intron 26 12,21,22 179del 9 Exon 2 20 179-195del Exon 2 22 960del C Exon 8 41 1944del22 Exon 16 This study 1995delG Exon 16 22 2322delC Exon 18 22 2542delG Exon 19 41 3775delT Exon 27 This study 4104delC Exon 29 22 4182delG Exon 29 This study 938-939insT Exon 8 22 4220insAGAA Exon 30 This study Large deletion Exons 23-29 21, This study Exon 15 22 ABCC1, ABCC6 41, this study Mutation types The mutation types found in this study are summarized in Table 1. Login to comment
43 We found eight different missense mutations (R765Q, R1114H, T1130M, R1221C, A1303P, G1302R, K1394N, R1459C) that occurred in various combinations in nine alleles of eight patients. Login to comment

PMID: 12850230 [PubMed] Hu X et al: "Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update."

No. Sentence Comment

193 TABLE 3 Summary of ABCC6 Mutations in PXE Patients Mutation Protein Alteration Nucleotide Substitution Location Reference Nonsense Q378X 1132C Ͼ T Exon 9 16,107 R518X 1552C Ͼ T Exon 12 88 Y768X 2304C Ͼ A Exon 18 67 R1030X 3088C Ͼ T Exon 23 67 R1141X 3421C Ͼ T Exon 24 12,45,67,107,111,112,133 R1164X 3490C Ͼ T Exon 24 88,112 Q1237X 3709C Ͼ T Exon 26 67 R1398X 4192C Ͼ T Exon 29 67 Missense T364R 1091C Ͼ G Exon 9 107 N411K 1233T Ͼ G Exon 10 67 A455P 1363G Ͼ C Exon 11 142 R518Q 1553G Ͼ A Exon 12 67,142 F568S 1703T Ͼ C Exon 13 67 L673P 2018T Ͼ C Exon 16 67 R765Q 2294G Ͼ A Exon 18 67 R1114P 3341G Ͼ C Exon 24 67 S1121W 3362C Ͼ G Exon 24 67 R1138W 3412C Ͼ T Exon 24 111 R1138Q 3413G Ͼ A Exon 24 67,111 R1138P 3413G Ͼ C Exon 24 67 G1203D 3608G Ͼ A Exon 25 67 V1298F 3892G Ͼ T Exon 28 67 T13011 3902C Ͼ T Exon 28 67 G1302R 3904G Ͼ A Exon 28 67 A1303P 3907G Ͼ C Exon 28 67 R1314W 3940C Ͼ T Exon 28 67 R1314Q 3941G Ͼ A Exon 28 67 G1321S 3961G Ͼ A Exon 28 67 R1339C 4015C Ͼ T Exon 28 67,133 Q1347H 4041G Ͼ C Exon 28 67 G1354R 4060G Ͼ C Exon 29 107,142 D1361N 4081G Ͼ A Exon 29 67 11424T 4271T Ͼ C Exon 30 67 Frameshift Splicing IVS21 ϩ 1G ϾT Intron 21 67,142 IVS26-1G ϾA Intron 26 67,111,112 Deletion 179del9 Exon 2 107 179-195del Exon 2 67 960delC Exon 8 88 1944del22 Exon 16 12 1995delG Exon 16 67 2322delC Exon 18 67 2542delG Exon 19 67 3775delT Exon 27 12,67 4101delC Exon 29 67 Insertion 938-939insT Exon 8 67 4220insAGAA Exon 30 12 Intragenic deletion Exon 23-29 67,112 Exon 15 67 Intergenic deletion ABCC6 12,88 LOCAL RETINAL TRANSPORT FUNCTION OF ABCC6 ABCC6 Expression in the Retina Bergen et al detected ABCC6 expression in various tissues in man.12 Low expression levels of ABCC6 were observed in the retina as well as other tissues usually affected by PXE, including skin and vessel wall. Login to comment

PMID: 15645653 [PubMed] Noji Y et al: "Identification of two novel missense mutations (p.R1221C and p.R1357W) in the ABCC6 (MRP6) gene in a Japanese patient with pseudoxanthoma elasticum (PXE)."

No. Sentence Comment

74 In vitro transport studies with three PXE-causing mutants (p.V1298F, p.G1302R and p.G1321S) within NBD2, that had been expressed in Sf9 cells, showed markedly reduced transport activities (12). Login to comment

PMID: 15727254 [PubMed] Hu X et al: "Efficient molecular diagnostic strategy for ABCC6 in pseudoxanthoma elasticum."

No. Sentence Comment

57 Six nucleotide changes, including 2,294g Ǟ a (R765Q in exon 18), 3,421c Ǟ t (R1141X in exon 24), 3904g Ǟ a (G1302R in exon 28), 3,907g Ǟ c (A1303P in exon 28), 3,775del T (W1259 frameshift in exon 27), and 4,377c Ǟ t (R1459C in exon 30) were determined by the digestion of PCR fragments with restriction enzymes Sma I, Bsi YI, Nci I, Hea III, Bst NI, and Aci I, respectively. Login to comment
95 RESULTS OF THE MUTATION ANALYSIS IN THE ABBC6 GENE IN 76 PATIENTS Sequence Type AA change variation Location Alleles Statusa Phaseb Method Nonsense Q749X 2247 C → T Exon 17 2 ht 3 DHPLC R1141X 3421 C → T Exon 24 35 hm.ht.ch 1 Bsi YI Missense R765Q 2294G → A Exon 18 1 ht 2 Sma I R1114H 3341G → A Exon 24 1 ht 3 dHPLC T1130M 3390C → T Exon 24 2 ch 3 dHPLC R1221C 3663C → T Exon 26 1 ch 3 dHPLC G1302R 3904G → A Exon 28 1 ht 2 Nci I A1303P 3907G → C Exon 28 1 ch 2 Hae III D1326N 3999G → A Exon 28 1 ht 3 dHPLC K1394N 4182G → T Exon 29 1 ch 3 dHPLC R1459C 4377C → T Exon 30 1 ht 2 Aci I Frameshift Splicing IVS17-12delTT Intron 17 1 ht 3 dHPLC IVS26-1G → A Intron 26 1 ht 3 dHPLC Deletion 1944del22 Exon 16 2 ht,ch 2 PCR 4182delG Exon 29 6 hm,ht 3 dHPLC 3775delT Exon 27 11 hm,ht 2 Bst NI 3821del48 Exon 27 1 ht 2 PCR Insertion 4220insAGAA Exon 30 1 ht 3 dHPLC Deletion A995del405 del exon 23-29 Exon 23-29 17 hm,ht,ch,hem 1 PCR ABCC6 2 ht 4 FISH ahm, homozygote; ht, heterozygote; ch, compound heterozygote; hem, hemizygote. Login to comment
157 Next, R765Q, G1302R, A1303P, 3775 del T, and R1459C mutations were detected in 15 mutant alleles by digestion of PCR fragments with restriction enzymes Sma I, Nci I, Hae III, Bst NI, and Aci I, respectively. Login to comment

PMID: 15894595 [PubMed] Chassaing N et al: "Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations."

No. Sentence Comment

378 Interestingly, among the 49 different missense mutations in ABCC6 (42 previously published and seven new ones in the present study), the majority (43) replace critical amino acids in intracellular domains (seven and 19 mutations are located in I1424T R1459C 4220insAGAA 4318delA G1354R D1361N K1394N E1400K R1298X 410delC 418delG 3775delT R1275X R1221C D1238H W1223X Q1237X IVS26-1G→A R1114C R1114H R1114P S1121W M1127T T1130M R1138P R1138Q R1138W R1141X R1164X R765Q A766D Y768X A781V 2322delC IVS19-2delAG T364R R391G Q378X Q363_R373del 938_939insT 960delC IVS8+2delTG G199X Y227X 179_195del 179_187del G226R V74del Q749X IVS17-12delTT IVS14-5T→G IVS13-29T→A R600G V1298F G1299S T1301I G1302R A1303P S1307P R1314Q R1314W G1321S L1335P R1339C P1346S Q1347H R1030X F1048del R807Q V810M A820P 254delG L673P 1944_1966del 1995delG R518Q R518X K502M A455P G992R IVS21+1G→T G1203DF568SN411K C440G IVS25-3C→A 3544dupC Ex23_29del 30 Ex15del ABCC6del 252015105 Figure 10 Position of the mutations in the ABCC6 gene. Login to comment
379 Table 2 ABCC6 mutations Nucleotide variation Protein alteration Location (gene ) Location (protein) Reference Missense 676 GRA G226R Exon 7 CL 3 This study 1091 CRG T364R Exon 9 TS 7 63, 78 1171 ARG R391G Exon 9 CL 4 88 1233 TRG N411K Exon 10 CL 4 63, 90 1318 TRG C440G Exon 10 TS 8 63 1363 GRC A455P Exon 11 TS 9 86 1505 ART K502M Exon 12 CL 5 This study 1553 GRA R518Q Exon 12 CL 5 63, 86, 88, 90 1703 TRC F568S Exon 13 ECL 5 90 1798 CRT R600G Exon 14 CL 6 63 2018 TRC L673P Exon 16 NBF 1 90 2294 GRA R765Q Exon 18 NBF 1 87, 90 2297 CRA A766D Exon 18 NBF 1 88 2342 CRT A781V Exon 18 NBF 1 This study 2420 GRA R807Q Exon 19 NBF 1 This study 2428 GRA V810M Exon 19 NBF1 63 2458 GRC A820P Exon 19 NBF1 63 2965 GRC G992R Exon 22 ECL 6 This study 3340 CRT R1114C Exon 24 CL 8 63 3341 GRA R1114H Exon 24 CL 8 87 3341 GRC R1114P Exon 24 CL 8 90 3362 CRG S1121W Exon 24 CL 8 90 3380 CRT M1127T Exon 24 CL 8 63 3389 CRT T1130M Exon 24 CL 8 63, 87, 88 3412 CRT R1138W Exon 24 CL 8 17 3413 GRC R1138P Exon 24 CL 8 90 3413 GRA R1138Q Exon 24 CL 8 17, 63, 88, 90 3608 GRA G1203D Exon 25 TS17 90 3663 CRT R1221C Exon 26 COOH 87 3712 GRC D1238H Exon 26 COOH 88 3892 GRT V1298F Exon 28 NBF 2 90 3895 GRA G1299S Exon 28 NBF 2 This study 3902 CRT T1301I Exon 28 NBF 2 90 3904 GRA G1302R Exon 28 NBF 2 87, 90 3907 GRC A1303P Exon 28 NBF 2 87, 90 3919 TRC S1307P Exon 28 NBF 2 This study 3940 CRT R1314W Exon 28 NBF 2 90 3941 GRA R1314Q Exon 28 NBF 2 90 3961 GRA G1321S Exon 28 NBF 2 90 4004 TRC L1335P Exon 28 NBF 2 88 4015 CRT R1339C Exon 28 NBF 2 18, 63, 90 4036 CRT P1346S Exon 28 NBF 2 63 4041 GRC Q1347H Exon 28 NBF 2 90 4060 GRC G1354R Exon 29 NBF 2 78, 86 4081 GRA D1361N Exon 29 NBF 2 90 4182 GRT K1394N Exon 29 NBF 2 87 4198 GRA E1400K Exon 29 NBF 2 63, 88 4271 TRC I1424T Exon 30 NBF 2 90 4377 CRT R1459C Exon 30 NBF 2 87 Nonsense 595 CRT G199X Exon 5 89 681 CRG Y227X Exon 7 84 1132 CRT Q378X Exon 9 63, 78, 83 1552 CRT R518X Exon 12 63, 84, 88 2245 CRT Q749X Exon 17 87 2304 CRA Y768X Exon 18 90 3088 CRT R1030X Exon 23 63, 90 3421 CRT R1141X Exon 24 15, 17, 18, 63, 78, 85, 87, 88, 90 3490 CRT R1164X Exon 24 84, 85, 88 3668 GRA W1223X Exon 26 88 3709 CRT Q1237X Exon 26 90 3823 CRT R1275X Exon 27 63 4192 CRT R1398X Exon 29 90 Splicing alteration IVS8+2delTG Intron 8 This study IVS13-29 TRA Intron 13 This study IVS14-5 TRG Intron 14 This study IVS17-12delTT Intron 17 87 IVS18-2delAG Intron 17 63 IVS21+1 GRT Intron 21 86, 90 IVS25-3 CRA Intron 25 88 IVS26-1 GRA Intron 26 17, 63, 90 Insertion 938_939insT Frameshift Exon 8 90 3544dupC Frameshift Exon 25 63 4220insAGAA Frameshift Exon 30 15, 87 Small deletion 179_187del Frameshift Exon 2 78 179_195del Frameshift Exon 2 90 Pseudoxanthoma elasticum www.jmedgenet.com NBF1 and NBF2, respectively), four are located in transmembrane domains, and only two mutations have been identified in extracellular domains. Login to comment

PMID: 17617515 [PubMed] Pfendner EG et al: "Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum."

No. Sentence Comment

254 Collectively, the mutations in exons 24 and 28, including the common mutations R1141X and del 23-29, accounted for 71.5% of all the 316 mutations identified in this study (table 2), and the 11 most prevalent mutations (R1141X, del23-29, R1339C, R1164X, 2787+1GRT, G1302R, R1138Q, R1138W, Q378X, R1314W, R518Q) accounted for 70% (223 of 316) of the mutant alleles identified (table 2). Login to comment
296 Molecular studies of three different MRP6 missense mutations (V1298F, G1302R and G1321S) performed in vitro found that none of these three mutations resulted in ATP-dependent substrate transport although ATP binding was normal.11 Although these in vitro data do not address whether the proteins bearing these missense mutations are actually formed in the cell and inserted properly into the membrane, it confirms the hypothesis that a missense mutation in a critical portion of the molecule can completely ablate the function of the protein and result in a phenotype as severe as if no protein was present at all. Login to comment
262 Genotype-phenotype correlations The comparison of subjects whose mutations would probably have resulted in no functional protein with those whose mutations would probably have resulted in some functional Table 2 Distinct mutations identified in the international case series of 271 patients with PXE Nucleotide change*À Predicted consequenceÀ Frequency (alleles) Exon-intron location Domain affected` Mutant alleles (%) References1 c.105delA p.S37fsX80 2 2 0.6 28 c.177-185del9 p.R60_Y62del 1 2 0.3 9, 28 c.179del12ins3 p. R60_W64del L60_R61ins 1 2 0.3 c.220-1gRc SJ 1 IVS 2 0.3 c.724gRt p.E242X 1 7 0.3 c.938insT FS 1 8 0.3 25 c.998+2delT SJ 1 IVS 8 0.3 2, 21 c.998+2del2 SJ 1 IVS 8 0.3 18 c.951cRg p.S317R 2 9 TM6 0.6 28 c.1087cRt p.Q363X 1 9 0.3 c.1091gRa p.T364R 1 9 TM7 0.3 9, 19, 21, 28 c.1132cRt p.Q378X 4 9 1.2 9, 17-19, 28, 37 c.1144cRt p.R382W 2 9 IC4 0.6 c.1171aRg p.R391G 3 9 IC4 0.9 9, 18, 28, 37 c.1176gRc p.K392N 1 9 IC4 0.3 c.1388tRa p.L463H 1 11 TM9 0.3 c.1484tRa p.L495H 1 12 IC5 0.3 28 c.1552cRt p.R518X 2 12 0.6 18, 19, 27, 28, 37 c.1553gRa p.R518Q 4 12 IC5 1.2 18, 19, 24, 28, 31 c.1603tRc p.S535P 1 12 TM10 0.3 c.1703tRc p.F568S 1 13 TM11 0.3 24 c.1798cRt p.R600C 1 14 TM11 0.3 c.1857insC FS 1 14 0.3 c.1987gRt p.G663C 1 16 NBF1 0.3 c.1999delG FS 1 16 0.3 c.2070+5GRA SJ 2 IVS 16 0.6 c.2093aRc p.Q698P 2 17 NBF1 0.6 c.2097gRt p.E699D 1 17 NBF1 0.3 c.2177tRc p.L726P 1 17 NBF1 0.3 c.2237ins10 FS 2 17 0.6 c.2252tRa p.M751K 1 18 NBF1 0.3 20, 37 c.2263gRa p.G755R 2 18 NBF1 0.6 c.2278cRt p.R760W 3 18 NBF1 0.9 20, 28, 32, 37 c.2294gRa p.R765Q 2 18 NBF1 0.6 20-22, 25, 28, 32, 37 c.2329gRa p.D777N 1 18 NBF1 0.3 c.2359gRt p.V787I 1 18 NBF1 0.3 c.2432cRt p.T811M 1 19 IC6 0.3 6 c.2643gRt p.R881S 1 20 IC6 0.3 c.2787+1GRT SJ 9 IVS 21 2.8 17, 20, 24, 28, 31, 37 c.2814cRg p.Y938X 1 22 0.3 c.2820insC FS 1 22 0.3 c.2831cRt p.T944I 1 22 TM12 0.3 c.2848gRa p.A950T 1 22 TM12 0.3 c.2974gRc p.G992R 1 22 TM13 0.3 2, 42 c.3340cRt p.R1114C 2 24 IC8 0.6 19, 28, 32, 37, 41 c.3389cRt p.T1130M 3 24 IC8 0.9 18, 19, 21, 22, 28, 30, 32, 37, 41 c.3398gRc p.G1133A 1 24 IC8 0.3 c.3412gRa p.R1138W 7 24 IC8 2.2 28, 30, 37 c.3413cRt p.R1138Q 7 24 IC8 2.2 18, 19, 24, 25, 28, 30, 32, 37, 41 c.3415gRa p.A1139T 2 24 IC8 0.6 c.3415gRa & c.2070+5GRA* p.A1139T & SJ 1 24, IVS 16 IC8 0.3 c.3415gRa & c.4335delG* p.A1139T & FS 1 24, 30 IC8 0.3 c.3421cRt p.R1141X 92 24 29.3 5, 9, 15,18, 19, 21, 22, 24, 28, 30-32, 33, 37, 41 c.3427cRt p.Q1143X 1 24 0.3 c.3490cRt p.R1164X 15 24 4.7 18, 27, 28, 31, 33 c.3491gRa p.R1164Q 1 24 IC8 0.3 28 c.3661cRt p.R1221C 1 26 IC9 0.3 21, 22, 28, 29 c.3662gRa p.R1221H 2 26 IC9 0.6 40 c.3676cRa p.L1226I 1 26 IC9 0.3 c.3722gRa p.W1241X 2 26 0.6 c.3774insC FS 2 27 0.6 c.3775delT p.G1259fsX1272 3 27 0.9 15, 25, 28, 41 c.3880-3882del p.K1294del 1 27 0.3 c.3883-5GRA SJ 1 IVS 27 0.3 c.3892gRt p.V1298F 1 28 NBF2 0.3 25 c.3904gRa p.G1302R 7 28 NBF2 2.2 21, 22, 25, 28 c.3907gRc p.A1303P 1 28 NBF2 0.3 21, 22, 25, 28 c.3912delG FS 1 28 0.3 28 c.3940cRt p.R1314W 4 28 NBF2 1.2 24, 25, 32, 36 c.3941gRa p.R1314Q 1 28 NBF2 0.3 25, 28, 32, 36, 41 c.4004tRa p.L1335Q 1 28 NBF2 0.3 c.4015cRt p.R1339C 16 28 NBF2 5.0 19, 25, 28, 33 c.4016gRa p.R1339H 2 28 NBF2 0.6 c.4025tRc p.I1342T 1 28 NBF2 0.3 protein did not yield significant differences. Login to comment

PMID: 19133228 [PubMed] Fulop K et al: "Clustering of disease-causing mutations on the domain-domain interfaces of ABCC6."

No. Sentence Comment

67 It is worth to note that we have expressed G1302R in Sf9 insect cell and found that the ATP-driven transport activity due to the mutations was lost [6]. Login to comment

PMID: 19339160 [PubMed] Ramsay M et al: "Spectrum of genetic variation at the ABCC6 locus in South Africans: Pseudoxanthoma elasticum patients and healthy individuals."

No. Sentence Comment

121 of alleles with mutation Frequency R1339C c.4015C>T 28 NBF2 18 0.375 21 0.447 0.411 (39) [30-32] R1138Q c.3413G>A 24 CL8 5 0.104 1 0.021 0.063 (6) [3,7,32] Y768X c.2304C>A 18 NBF1 5 0.104 3 0.064 0.084 (8) [31] R1141X c.3421C>T 24 CL8 4 0.083 5 0.106 0.095 (9) [3,6,13] R518Q c.1553G>A 12 CL5 2 0.042 1 0.021 0.032 (3) [31-33] Deletion ABCC6del23-29 23-29 - 1 0.021 2 0.043 0.032 (3) [6,16,31,32] L1335P c.4004T>C 28 NBF2 2 0.042 - - Other = 0.063 (6) [3] G1302R c.3904G>A 28 NBF2 1 0.021 - - [31] L726P c.2177T>C 17 NBF1 1 0.021 - - This Study Frameshift c.3775delT 27 CL9 1 0.021 - - [6] Frameshift c.4104delC 29 NBF2 1 0.021 - - [31] Unknown - - - 7 0.146 14 0.298 0.221 (21) - Total 48 47 Mutation detection rate 0.855 0.702 0.717 a ''Coloured``, black and Indian patients are excluded from the table because of the small sample size. Login to comment
195 It detects 79.2% of the PXE mutations in white South African patients including: R1339C, R1138Q, Y768X, R1141X, R518Q, del23-29, L1335P and G1302R (calculated according to detection Strategy 1, Table 1). Login to comment

PMID: 16763870 [PubMed] Ladewig MS et al: "[Pseudoxanthoma elasticum]."

No. Sentence Comment

272 Internetadressen PXE-Selbsthilfegruppe Deutschland : http://www.pxe-groenblad.de PXE International: http://www.pxe.org Tabelle 5 PXE verursachende Mutationen imabcc6-Gen Klassifikation Lokalisation Gen Protein Missense Exon 9 Exon 9 Exon 10 Exon 10 Exon 11 Exon 12 Exon 13 Exon 14 Exon 16 Exon 18 Exon 18 Exon 18 Exon 18 Exon 19 Exon 19 Exon 19 Exon 22 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 25 Exon 26 Exon 26 Exon 26 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 29 Exon 29 Exon 29 Exon 29 Exon 29 Exon 30 Exon 30 Exon 30 c.1091CaG c.1171AaG c.1233TaG c.1318TaG c.1363GaC c.1553GaA c.1703TaC c.1798CaT c.2018TaC c.2252TaA c.2278CaT c.2294GaA c.2297CaA c.2428GaA c.2458GaC c.2552TaC c.2855TaG c.3340CaT c.3341GaA c.3341GaC c.3362CaG c.3380CaT c.3389CaT c.3412CaT c.3413GaA c.3413GaC c.3608GaA c.3661CaT c.3712GaC c.3715TaC c.3892GaT c.3902CaT c.3904GaA c.3907GaC c.3932GaA c.3940CaT c.3941GaA c.3961GaA c.3976GaA c.4004TaC c.4015CaT c.4036CaT c.4041GaC c.4060GaC c.4069CaT c.4081GaA c.4182GaT c.4198GaA c.4209CaA c.4271TaC c.4377CaT p.T364R p.R391G p.N411K p.C440G p.A455P p.R518Q p.F568S p.R600G p.L673P p.M751K p.R760W p.R765Q p.A766D p.V810M p.A820P p.L851P p.F952C p.R1114C p.R1114H p.R1114P p.S1121W p.M1127T p.T1130M p.R1138W p.R1138Q p.R1138P p.G1203D p.R1221C p.D1238H p.Y1239H p.V1298F p.T1301I p.G1302R p.A1303P p.G1311E p.R1314W p.R1314Q p.G1321S p.D1326N p.L1335P p.R1339C p.P1346S p.Q1347H p.G1354R p.R1357W p.D1361N p.K1394N p.E1400K p.S1403R p.I1424T p.R1459C Klassifikation Lokalisation Gen Protein Nonsense Exon 9 Exon 12 Exon 17 Exon 18 Exon 23 Exon 24 Exon 24 Exon 26 Exon 26 Exon 27 Exon 29 c.1132CaT c.1552CaT c.2247CaT c.2304CaA c.3088CaT c.3421CaT c.3490CaT c.3668GaA c.3709CaT c.3823CaT c.4192CaT p.Q378X p.R518X p.Q749X p.Y768X p.R1030X p.R1141X p.R1164X p.W1223X p.Q1237X p.R1275X p.R1398X Spleißstellen Intron 21 Intron 25 Intron 26 c.2787+1GaT c.3634-3CaA c.3736-1GaA Insertion Exon 8 Exon 25 Exon 30 c.938-939insT c.3544dupC c.4220insAGAA Deletion Exon 2 Exon 2 Exon 3 Exon 8 Exon 9 Exon 16 Exon 16 Exon 18 Exon 19 Exon 22 Exon 27 Exon 29 Exon 29 Exon 30 Exon 31 c.179del9 c.179-195del c.220-222del c.960delC c.1088-1120del c.1944del22 c.1995delG c.2322delC c.2542delG c.2835-2850del16 c.3775delT c.4101delC c.4182delG c.4318delA c.4434delA Intragenische Deletion Exon 15 Exon 18 Exon 23-29 delEx15 delEx18 delEx23-29 Intergenische Deletion ABCC6 delABCC6 Fazit für die Praxis Eine spezifische Behandlung der Grunderkrankung ist nicht bekannt. Login to comment

PMID: 17251343 [PubMed] Shi Y et al: "Development of a rapid, reliable genetic test for pseudoxanthoma elasticum."

No. Sentence Comment

82 Nuclease Digestion Fragment Sizes of Common Mutations in PXE Exon 24 and 28 Amino acid change Base change Fragment lengths (bp) p.T1130M c.3389CϾT 251,257/508 p.R1138W c.3412CϾT 274,234/508 p.R1138Q c.3413GϾA 275,233/508 p.R1141X c.3421CϾT 281,227/508 p.R1164X c.3490CϾT 352,156/508 p.G1302R c.3904GϾA 116,289/405 p.R1314Q c.3941GϾA 153,252/405 p.R1339C c.4015CϾT 227,178/405 The total lengths of the amplicons are listed after the slash. Login to comment
84 Patients 5 and 16 each had a mutation corresponding to c.4015CϾT (p.R1339C) (cleavage fragments of ϳ180 and ϳ230 bp), and patients 8 and 9 had one mutation corresponding to c.3904GϾA (p.G1302R) (fragments of ϳ120 and ϳ290 bp). Login to comment

PMID: 20799350 [PubMed] Kelly L et al: "Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains."

No. Sentence Comment

30 Mutations in the ATP-binding site also disrupt function, such as G1302R in the Pseudoxanthoma elasticum- associated ABCC6 gene.15 Finally, mutations such as the Dubin-Johnson syndrome-associated Q1382R in ABCC2 are in a mobile region of the NBD (the ''Q-loop``) that is hypothesized to transmit a conformational change between the NBDs and TMDs of an ABC transporter.16 While it is preferable to experimentally characterize the effects of each of the thousands of reported variants in ABC transporters, this approach is not feasible given the large number of variants. Login to comment