ABCMdb

PMID: 15894595

Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A
Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.
J Med Genet. 2005 Dec;42(12):881-92. Epub 2005 May 13., [PubMed]

Sentences

No. Mutations Sentence Comment

378 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.Tyr227* ABCC6 p.Arg518* ABCC6 p.Gln378* ABCC6 p.Gln1347His 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.Ala1303Pro ABCC6 p.Leu673Pro ABCC6 p.Thr1301Ile 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 ABCC6 p.Ala766Asp ABCC6 p.Asp1238His ABCC6 p.Leu1335Pro ABCC6 p.Trp1223* ABCC6 p.Arg391Gly ABCC6 p.Glu1400Lys ABCC6 p.Gly226Arg ABCC6 p.Arg807Gln ABCC6 p.Ala781Val ABCC6 p.Gly1299Ser ABCC6 p.Lys502Met ABCC6 p.Val810Met ABCC6 p.Cys440Gly ABCC6 p.Arg1114Cys ABCC6 p.Gly992Arg ABCC6 p.Pro1346Ser ABCC6 p.Met1127Thr ABCC6 p.Ala820Pro ABCC6 p.Ser1307Pro ABCC6 p.Arg1275* ABCC6 p.Arg600Gly 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 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.Tyr227* 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.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.Arg1459Cys ABCC6 p.Arg1221Cys ABCC6 p.Gln749* ABCC6 p.Arg1114His ABCC6 p.Lys1394Asn ABCC6 p.Ala766Asp ABCC6 p.Asp1238His ABCC6 p.Leu1335Pro ABCC6 p.Trp1223* ABCC6 p.Arg391Gly ABCC6 p.Glu1400Lys ABCC6 p.Gly226Arg ABCC6 p.Ala781Val ABCC6 p.Gly1299Ser ABCC6 p.Lys502Met ABCC6 p.Val810Met ABCC6 p.Cys440Gly ABCC6 p.Arg1114Cys ABCC6 p.Gly992Arg ABCC6 p.Pro1346Ser ABCC6 p.Met1127Thr ABCC6 p.Ala820Pro ABCC6 p.Ser1307Pro ABCC6 p.Arg1275* ABCC6 p.Arg600Gly 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 383 ABCC6 p.Arg1141* Although most of the 90 pathogenic mutations have been identified in one or a limited number of families, two variants (Ex23_29del and R1141X) are recurrent mutations. Login to comment 384 ABCC6 p.Arg1141* ABCC6 p.Arg1141* The frequency of these two recurrent mutations differs according to the population studied: mutation Ex23_29del represents ,28% of the detected mutations in the US population and ,4% in the European population, whereas mutation R1141X represents ,4% of the detected mutations in the US population and ,28% in the European population.90 Furthermore, frequency of the R1141X differs between European countries (for example, 30% in the Dutch population,91 92 26% in Italian patients,63 and 13% in the French population88 ). Login to comment 385 ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg518Gln ABCC6 p.Arg518* ABCC6 p.Gln378* ABCC6 p.Arg1339Cys A common founder effect was identified for mutation R1141X in French and Italian populations.63 88 We found that arginine codon 518 was a recurrently mutated amino acid in a cohort of 19 French families with PXE (11.5% of the detected mutations for each variant R518Q and R518X).88 These two mutations represent 19% of the mutations detected in the Italian population.63 In Japanese patients, neither R1141X nor Ex23_29del mutations were identified, whereas mutations 2542delG and Q378X account for 53% and 25%, respectively.93 In South African families of Afrikaaners, mutation R1339C represents more than half the mutations detected,28 with a common haplotype indicating a founder effect.27 28 These mutations are rarely identified in American or European populations.90 The detection rate in different studies varies from 0.55 to 0.83.63 87 88 90 Lack of mutation detection in some patients could reflect exonic deletions (for example, deletion of exon 15), splice site mutations distant from the coding sequence, mutations in the gene regulatory sequences, or investigation of patients with acquired PXE-like syndrome not related to ABCC6 mutations, such as seen in b thalassaemia and sickling syndromes (see below).94 95 Locus heterogeneity of PXE is unlikely, but cannot currently be ruled out. Login to comment 399 ABCC6 p.Arg1141* ABCC6 p.Arg1141* * In 2002, Trip et al reported that the prevalence of the sole R1141X mutation was significantly increased in young individuals with coronary artery disease (3.2%), but was also frequent in the general Dutch population.100 They identified eight heterozygous carriers for mutation R1141X among 1057 controls (0.76%). Login to comment 409 ABCC6 p.Arg1141* A few reports have emphasised the carriage of a sole ABCC6 mutation as a cardiovascular risk factor.70 100 102 In the study by Trip et al, mutation R1141X in ABCC6 appeared to be an independent risk factor for coronary heart disease in young people.100 This observation, if confirmed in other similar cohorts, could be of course of considerable concern for public health. Login to comment