ABCMdb

PMID: 12673275

Hu X, Plomp A, Wijnholds J, Ten Brink J, van Soest S, van den Born LI, Leys A, Peek R, de Jong PT, Bergen AA
ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum.
Eur J Hum Genet. 2003 Mar;11(3):215-24., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCC6 p.Arg1141* The R1141X mutation was by far the most common mutation identified in 19 (32.2%) patients. Login to comment 30 ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Gly1302Arg ABCC6 p.Arg765Gln ABCC6 p.Ala1303Pro ABCC6 p.Thr1130Met ABCC6 p.Thr1130Met ABCC6 p.Arg1459Cys ABCC6 p.Arg1221Cys ABCC6 p.Gln749* ABCC6 p.Gln749* ABCC6 p.Arg1114His ABCC6 p.Lys1394Asn 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 ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg1138Trp ABCC6 p.Arg1164* ABCC6 p.Arg518Gln ABCC6 p.Arg1114Pro ABCC6 p.Ala455Pro ABCC6 p.Arg1314Trp ABCC6 p.Arg518* ABCC6 p.Gln378* ABCC6 p.Gln1347His ABCC6 p.Phe568Ser ABCC6 p.Arg1398* ABCC6 p.Gly1321Ser ABCC6 p.Gly1302Arg ABCC6 p.Arg765Gln ABCC6 p.Ile1424Thr ABCC6 p.Val1298Phe ABCC6 p.Ser1121Trp ABCC6 p.Arg1030* ABCC6 p.Arg1339Cys ABCC6 p.Gln1237* ABCC6 p.Gly1203Asp ABCC6 p.Ala1303Pro ABCC6 p.Leu673Pro ABCC6 p.Thr1301Ile ABCC6 p.Asn411Lys ABCC6 p.Arg1138Pro ABCC6 p.Arg1314Gln ABCC6 p.Asp1361Asn ABCC6 p.Tyr768* ABCC6 p.Thr364Arg ABCC6 p.Gly1354Arg ABCC6 p.Thr1130Met ABCC6 p.Arg1459Cys ABCC6 p.Arg1221Cys ABCC6 p.Gln749* ABCC6 p.Arg1114His ABCC6 p.Lys1394Asn 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 39 ABCC6 p.Arg1141* ABCC6 p.Gln749* We observed two distinct nonsense mutations, R1141X and Q749X in 24 out of 117 alleles (20.5%). Login to comment 40 ABCC6 p.Arg1141* R1141X occurred in 22/117 alleles (18.8%) and was found in a homozygous, heterozygous, or compound heterozygous form in 19 patients (32.2%). Login to comment 42 ABCC6 p.Gln749* The Q749X nonsense mutation occurred in only two PXE patients in heterozygous or compound heterozygous form. Login to comment 43 ABCC6 p.Gly1302Arg ABCC6 p.Arg765Gln ABCC6 p.Ala1303Pro ABCC6 p.Thr1130Met ABCC6 p.Arg1459Cys ABCC6 p.Arg1221Cys ABCC6 p.Arg1114His ABCC6 p.Lys1394Asn 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 52 ABCC6 p.Arg1141* The latter deletion was found on 13 alleles (11.1%) of 11 patients (18.6%) and was the second most frequent mutation in this study after R1141X. Login to comment 69 ABCC6 p.Arg1141* The R1141X mutation, the most common PXE mutation found in our cohort, is located in this domain. Login to comment 76 ABCC6 p.Arg1141* Molecular analysis revealed that she was homozygous for the ABCC6/MRP6 R1141X mutation. Login to comment 83 ABCC6 p.Arg1495Cys In PXE patients of pedigree P 26095, detailed DNA and RNA analyses revealed one allele with a mutation (R1495C) as well as a wild-type allele. Login to comment 84 ABCC6 p.Arg1495Cys The R1495C mutation segregates through the maternal line, since a nephew of the mother carries the mutation also. Login to comment 95 ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1459Cys ABCC6 p.Arg1459Cys ABCC6 p.Arg1459Cys ABCC6 p.Arg1459Cys ABCC6 p.Arg1459Cys The family consisted of an affected mother, a healthy father, three severely affected, two mildly affected, Table 3 Clinical characteristics of patients from the pedigrees described in Figure 2 Genotype Pedigree Family member Age Age of onset Skin Biopsy Eyes Cardiovascular Allele 1 Allele 2 26101 II-1 44 12 + d AS ht,TIA R1141X R1141X I-1 69 n d n MI R1141X WT I-2 69 n d n Chest pain R1141X WT 26098 II-1 46 22 + d AS,MD GI hemorrhage delABCC6 del exon 23-29 II-2 40 n d AS n delABCC6 del exon 23-29 I-1 71 n 7 Drusen Multiple CI delABCC6 WT I-2 73 d d d MI del exon 23-29 WT 26095 I-3 83 52 + + AS,MD ht d II-1 66 n d n n WT WT II-2 63 48 + d MD n R1459C WT II-3 61 61 7 7 AS n R1459C WT II-4 59 n n AS,PdO n R1459C WT II-5 57 55 + d AS,neo,PdO n R1459C WT II-6 56 n d n n WT WT II-7 54 49 + d AS,neo n R1459C WT II-8 52 n d n n WT WT AS = angioid streaks; CI = cerebral infarct; GI = gastrointestinal; ht = hypertension; MD = macula degeneration; MI = myocardial infarct; n = normal; neo = neovascularization; PdO = peau d`orange; RD = retinal detachment; TIA = transient ischaemic attack; WT = wild type; + = affected; 7 = possibly affected; d = not tested. Login to comment 96 ABCC6 p.Arg1459Cys Figure 3 RT-PCR analysis of ABCC6 expression in leukcocytes in individuals homozygous and heterozygous for the R114X mutation and in individuals heterozygous for the R1459C mutation compared with wild-type ABCC6. Login to comment 99 ABCC6 p.Arg1141* The R1141X mutant allele leads to loss of a BsiYI restriction site; the mutated allele is therefore not cut and presents with a 500 bp band. Login to comment 100 ABCC6 p.Arg1495Cys ABCC6 p.Arg1495Cys (b) The R1495C mutation abolishes a AciI restriction site in the cDNA: Wild type sequences are cut and result in AciI fragments of 310 and 30 bp; R1495C mutated fragments result in a single AciI fragment of 340 bp. Login to comment 104 ABCC6 p.Arg1459Cys We detected an ABCC6/ MRP6 missense mutation (R1459C) heterozygously present in the DNA and RNA of all affected individuals. Login to comment 107 ABCC6 p.Arg1459Cys Restriction analysis of an RT-PCR product of exon 30 revealed the presence of the R1459C mutation in one transcript, while the other transcript was wild type (Figure 3). Login to comment 108 ABCC6 p.Arg1459Cys Sequencing of the entire ABCC6 cDNA in two patients (II-2, II-7) through RT-PCR of RNA from peripheral blood showed the presence of a mutated (R1459C), as well as an entirely normal, wild-type ABCC6 transcript, without mutations (not shown). Login to comment 109 ABCC6 p.Arg1459Cys We found the R1459C mutation also in the DNA of a maternal nephew, who, unfortunately, refused clinical examination (not shown). Login to comment 110 ABCC6 p.Arg1459Cys However, the latter finding provides further evidence that the R1459C mutation in this pedigree segregates via the maternal line to the affected children. Login to comment 128 ABCC6 p.Arg1141* ABCC6 p.Arg765Gln ABCC6 p.Arg1459Cys ABCC6 p.Arg1114His ABCC7 p.Arg560Thr ABCC7 p.Trp1204* ABCC2 p.Arg1150His ABCA4 p.Arg2077Trp ABCA4 p.His2128Arg ABCA4 p.Leu1631Pro Further alignment showed that the R765Q mutation in ABCC6/MRP6 is the positional equivalent of both the R560T mutation in ABCC7,28 and the R842G mutation in ABCC8.29 Similarly, additional possible positional equivalent clusters of conserved and mutated residues were found between ABCC6/ MRP6 and ABCC2 (R1114H and R1150H),30 ABCC6/MRP6 and ABCC7 (3775 del T and W1204X),31 ABCC6/MRP6 and ABCR (R1459C and H2128R, 4220InsAGAA and R2077W, R1141X and L1631P).32,33 Interestingly, for both ABCC7 and ABCR, models were postulated in which the severity of the disease shows an inverse correlation with the predicted transport activity of the ABC protein. Login to comment 138 ABCC6 p.Arg1459Cys In this study, we presented a novel family with an R1459C ABCC6/MRP6 mutation, in which ad segregation of PXE on the basis of clinical, molecular, and genealogical data, is the most likely explanation for our results. Login to comment 159 ABCC6 p.Arg1268Gln ABCC6 p.Val614Ala ABCC6 p.His632Gln ABCC6 p.Ala830Gly Table 4 Polymorphic sequence changes identified in ABCC6 Nucleotide Amino acid Location Estimated frequency (%) CA(18) F Intron4 68 V415V 1245G>A 10 33 V614A 1841T>C 14 52 T630T 1890C>G 15 22 H632Q 1896C>A 15 24 A830G 2490C>G 19 25 P945P 2846C>T 22 50 L968L 2904G>A 22 20 Int(22) F Intron22 50 R1268Q 3808G>A 27 38 The definition of disease-associated alleles essentially follows the criteria described by Le Saux et al.22 In summary, sequence variants predicted to result in nonsense or splice-site changes were considered to be disease-associated alleles if they are absent in DNA of a panel of at least 100 controls. Login to comment 165 ABCC6 p.Arg1141* ABCC6 p.Arg1459Cys The ABCC6/MRP6-specific RT-PCR primers used to analyse the mutations indicated were as follows: (R1141X): ABCC6/MRP6F, 50 -CTGTCTCCAAGCCATTGGGC- 30 (cDNA position 3008-3027) and ABCC6/MRP6R, 50 - AGCCACCAGTCGCGGGAAAC-30 (cDNA position 3524- 3505); (deletion exon 23-29): ABCC6/MRP6F3, 50 - ATACGGCAGGGTGAAGGCCA-30 (cDNA position 2801- 2820) and ABCC6/MRP6R3, 50 -CAGTGCACTGTGCAAAC CAGC-30 (cDNA position 4380-4360); (R1459C): ABCC6/ MRP6F4, 50 -CTGGCTCTCTGCGGATGAAC-30 (cDNA position 4081-4100); ABCC6/MRP6R4,50 -AGAACCCGGGCA CAGTCCAT-30 (cDNA position 4432-4413). Login to comment