ABCMdb

PMID: 17617515

Pfendner EG, Vanakker OM, Terry SF, Vourthis S, McAndrew PE, McClain MR, Fratta S, Marais AS, Hariri S, Coucke PJ, Ramsay M, Viljoen D, Terry PF, De Paepe A, Uitto J, Bercovitch LG
Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum.
J Med Genet. 2007 Oct;44(10):621-8. Epub 2007 Jul 6., [PubMed]

Sentences

No. Mutations Sentence Comment

187 ABCC6 p.Arg1141* Together with the recurrent R1141X and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Login to comment 200 ABCC6 p.Arg1141* Two recurrent mutations, R1141X and a large deletion of exons 23-29 (del23-29, p.A999_S1403del) have been described in a significant proportion of patients, leading to a mutation-detection strategy that first identifies the recurrent mutations by restriction-enzyme digestion, followed by sequencing of the remaining exons.39 In this study, we collected genotype data on 270 patients with PXE from 239 families and were able to characterise the phenotype in 198 of these patients to improve diagnosis, identify genotype-phenotype associations and facilitate genetic counselling of people at risk for PXE. Login to comment 211 ABCC6 p.Arg1141* Our mutation-detection strategy was based on: (1) identification of the recurrent mutations R1141X and del23-29 by restriction-enzyme digestion; (2) optimised denaturing high-performance liquid chromatography (dHPLC) scanning of PCR products corresponding to all exons in subjects in whom the two recurrent mutations were not identified on both alleles, followed by (3) sequencing of exons with altered dHPLC patterns; and (4) confirmation of novel mutations by restriction-enzyme digestion or resequencing. Login to comment 212 ABCC6 p.Arg1141* Screening for the recurrent mutations R1141X and del23-29 was performed as previously described.30 31 Conditions and primers for generating PCR products spanning all exons of the coding regions and flanking intronic sequences of the ABCC6 gene were identified for optimum dHPLC screening (supplementary table 1; available at http://jmg.bmj.com/supplemental). Login to comment 241 ABCC6 p.Arg1141* The two most common mutations were R1141X (29.3%, 92/316) and del23-29 (18%, 57/316). Login to comment 242 ABCC6 p.Arg1141* In all, 23 subjects (9.6%) were homozygous for either the R1141X (n = 11) or del23-29 (n = 2) or compound heterozygous (n = 10) for these two mutations. Login to comment 248 ABCC6 p.Arg1164* ABCC6 p.Arg1339Cys Of these, R1339C, R1164X and 2787+1gRc represented 5.0%, 4.7% and 2.8%, respectively, of the 316 alleles identified. Login to comment 249 ABCC6 p.Arg1339Cys R1339C was common in the South African Afrikaner population (15 of 40 alleles, 37.5%) and rare in the European/American case series (1/238 alleles). Login to comment 250 ABCC6 p.Arg1164* ABCC6 p.Arg1339Cys The high incidence of R1339C in the South African population is probably due to a founder effect.26 Conversely, R1164X (0/40 alleles) and 2787+1gRc (0 of 40 alleles) were absent in the South African case series but were prevalent in the European and American patient populations. Login to comment 254 ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg1138Trp ABCC6 p.Arg1164* ABCC6 p.Arg518Gln ABCC6 p.Arg1314Trp ABCC6 p.Gln378* ABCC6 p.Gly1302Arg ABCC6 p.Arg1339Cys 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 262 ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg1138Trp ABCC6 p.Arg1164* ABCC6 p.Arg518Gln ABCC6 p.Arg1314Trp ABCC6 p.Arg518* ABCC6 p.Gln378* ABCC6 p.Phe568Ser ABCC6 p.Gly1302Arg ABCC6 p.Arg765Gln ABCC6 p.Val1298Phe ABCC6 p.Arg1339Cys ABCC6 p.Ala1303Pro ABCC6 p.Arg1314Gln ABCC6 p.Thr364Arg ABCC6 p.Thr1130Met ABCC6 p.Arg1221Cys ABCC6 p.Arg391Gly ABCC6 p.Met751Lys ABCC6 p.Arg1114Cys ABCC6 p.Gly992Arg ABCC6 p.Arg760Trp ABCC6 p.Arg1164Gln ABCC6 p.Thr811Met ABCC6 p.Arg1221His ABCC6 p.Leu726Pro ABCC6 p.Ser317Arg ABCC6 p.Leu1226Ile ABCC6 p.Thr944Ile ABCC6 p.Asp777Asn ABCC6 p.Arg382Trp ABCC6 p.Leu463His ABCC6 p.Arg1339His ABCC6 p.Arg881Ser ABCC6 p.Ala1139Thr ABCC6 p.Ala1139Thr ABCC6 p.Ala1139Thr ABCC6 p.Glu699Asp ABCC6 p.Lys392Asn ABCC6 p.Gln698Pro ABCC6 p.Tyr938* ABCC6 p.Ser535Pro ABCC6 p.Ala950Thr ABCC6 p.Leu1335Gln ABCC6 p.Arg600Cys ABCC6 p.Gln363* ABCC6 p.Val787Ile ABCC6 p.Gly663Cys ABCC6 p.Gly755Arg ABCC6 p.Trp1241* ABCC6 p.Gly1133Ala ABCC6 p.Leu495His ABCC6 p.Ile1342Thr ABCC6 p.Glu242* ABCC6 p.Gln1143* 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 277 ABCC6 p.Gln1347His ABCC6 p.Arg1398* ABCC6 p.Gly1481Ser ABCC6 p.Gly1501Ser Finally, there is the possibility that mutations in genes other than ABCC6 can Nucleotide change*À Predicted consequenceÀ Frequency (alleles) Exon-intron location Domain affected` Mutant alleles (%) References1 c.4041gRc p.Q1347H 1 28 NBF2 0.3 25 c.4104delC FS 1 29 0.3 25 c.4192cRt p.R1398X 2 29 0.6 25 c.4335delG FS 1 30 0.3 c.4441gRa p.G1481S 1 31 NBF2 0.3 c.4501gRa p.G1501S 1 31 NBF2 0.3 Ex23_29del p.A999_S1403del 57 23-29 18.0 15, 18, 21, 25, 27, 28, 31, 32, 37, 44, 45 FS, frameshift; IC, intracellular domain; IVS, intron; NBF, nucleotide binding fold; SJ, splice junction; TM, transmembrane domain. Login to comment 288 ABCC6 p.Arg1141* The recurrent mutations R1141X and del23-29 were the most prevalent, consistent with previous reports. Login to comment 296 ABCC6 p.Gly1321Ser ABCC6 p.Gly1302Arg ABCC6 p.Val1298Phe 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