ABCMdb

PMID: 15459974

Gheduzzi D, Guidetti R, Anzivino C, Tarugi P, Di Leo E, Quaglino D, Ronchetti IP
ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE).
Hum Mutat. 2004 Nov;24(5):438-9., [PubMed]

Sentences

No. Mutations Sentence Comment

64 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.Arg1141* 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.Arg1141* 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.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg518Gln ABCC6 p.Arg518Gln ABCC6 p.Arg518Gln ABCC6 p.Arg518Gln ABCC6 p.Arg518Gln ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Gln378* ABCC6 p.Gln378* ABCC6 p.Gln378* ABCC6 p.Gln378* ABCC6 p.Gln378* ABCC6 p.Arg1030* ABCC6 p.Arg1030* ABCC6 p.Arg1030* ABCC6 p.Arg1030* ABCC6 p.Arg1030* ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Asn411Lys ABCC6 p.Thr364Arg ABCC6 p.Thr1130Met ABCC6 p.Glu1400Lys ABCC6 p.Glu1400Lys ABCC6 p.Glu1400Lys ABCC6 p.Glu1400Lys ABCC6 p.Val810Met ABCC6 p.Cys440Gly ABCC6 p.Arg1114Cys ABCC6 p.Pro1346Ser ABCC6 p.Met1127Thr ABCC6 p.Ala820Pro ABCC6 p.Ala820Pro ABCC6 p.Arg1275* ABCC6 p.Arg1275* ABCC6 p.Arg1275* ABCC6 p.Arg600Gly PXE-causative Mutations Recognized (on one and both alleles) in Italian Patients Family/ Proband Affected subjects Age / gender Clinical score Tot Mutations* Allele 1 Allele 2 Mutation type 001 32 F S2,E2 4 p.R518Q p.T1130MI-3097 002 36 M S3,E2,V2,C2 9 p.R518Q p.T1130M I-3013 001 46 F S1,E3 4 p.R1339C None found I-3094 001 57 F S2,E2 4 p.C440G p.P1346S I-3103 001 57 M E2 2 p.V810M p.R1114C I-3076 001 57 F S2,E4,V3 9 p.R1339C p.R1339C I-3016 001 69 F S3,E2,V2 7 p.N411K p.R1138Q missense I-3082 001 23 M S1,E2 3 p.R518Q p.R1141X I-3074 001 27 F S2,E2 4 p.T364R p.R518X I-3015 001 27 F S2,E3 5 p.Q378X p.R600G I-3062 001 45 M S2,E4,V2 8 p.R1141X p.E1400K 001 50 F S1 1 p.R1275X p.E1400K 002 60 F S3,E3 6 p.R1275X p.E1400K I-3067 003 66 F S2,E2 4 p.R1275X p.E1400K 001 61 F S3,E2 4 p.R518Q p.R1141XI-3027 002 63 F S3,E4,V3 10 p.R518Q p.R1141X missense + nonsense 001 23 F S3,E2 5 p.R1141X p.R1141XI-3056** 002 32 M S2,E2 4 p.R1141X p.R1141X 001 27 F S1,E2 3 p.R1141X p.R1141XI-3057** 002 31 M S3,E2 5 p.R1141X p.R1141X 001 28 M S1,E2 3 p.R1141X None foundI-3045 002 32 F S3,E2,V1 6 p.R1141X None found I-3107 001 29 M S2,E1 3 p.R1030X p.R1141X I-3073 001 31 F S3,E2 5 p.R1141X p.R1141X I-3111 001 32 F S1,E2 3 p.R1141X p.R1141X I-3090 001 34 F S2,E1 3 p.R1141X p.R1141X I-3001 001 37 F S3,E2,V2 7 p.R1030X None found 001 40 F S2,E2 4 p.R1141X p.R1141XI-3007** 002 48 F S1,E2 3 p.R1141X p.R1141X I-3114 001 40 M S2,E2,V3,C1,G2 10 p.R518X p.R518X I-3054 001 44 F S2,E3 5 p.R518X p.R518X 001 47 F S3,E4,C2,G1 10 p.R1141X p.R1141XI-3055** 002 50 F S3,E3 6 p.R1141X p.R1141X 001 50 F S3,E4,V3,C2 12 p.R518X p.R1030X 002 52 F S3,E4,V3 10 p.R518X p.R1030X I-3017 003 55 F S3,E2 5 p.R518X p.R1030X I-3100 001 52 M S3,E3 6 p.Q378X p.Q378X I-3051 001 53 F S3,E4,V2 9 p.R1141X p.R1141X I-3034 001 53 M S3,E4,V3 10 p.R1141X p.R1141X I-3093 001 57 F S3,E3,V2,C3 11 p.R518X None found I-3087 001 57 F S3,E4,V2,C2 11 p.Q378X p.Q378X I-3040 001 60 F S3,E4,V2 9 p.R1141X None found I-3033 001 62 F S3,E4 7 p.R1141X p.R1141X nonsense I-3026 001 36 F S3,E2,G1 6 p.R518X c.2248-2_2248- 1del I-3024 001 40 F S1,E2,V3 6 p.R518X p.L1182PfsX96 I-3072 001 41 F S2,E2,C2 6 p.M1127T c.3736-1G>A I-3002 001 50 F S3,E2 5 p.A820P c.3736-1G>A others Family/ Proband Affected subjects Age / gender Clinical score Tot Mutations* Allele 1 Allele 2 Mutation type 002 57 F S2,E4 6 p.A820P c.3736-1G>A I-3008 001 53 F S2,E2,C1 5 p.M1440CfsX24 p.M1440CfsX24 Patients are identified by an international code: I = Italian, 3001 = family number (European patients are numerated from 3000), 001 = subject number. Login to comment 72 ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg518Gln ABCC6 p.Arg518* ABCC6 p.Gln378* ABCC6 p.Arg1030* ABCC6 p.Arg1339Cys ABCC6 p.Asn411Lys ABCC6 p.Thr364Arg ABCC6 p.Thr1130Met ABCC6 p.Glu1400Lys ABCC6 p.Val810Met ABCC6 p.Cys440Gly ABCC6 p.Arg1114Cys ABCC6 p.Pro1346Ser ABCC6 p.Met1127Thr ABCC6 p.Ala820Pro ABCC6 p.Arg1275* ABCC6 p.Arg600Gly ABCC6/MRP6 Mutations Found in Italian PXE Patients Number of families INTRON EXON cDNA* PROTEIN* References 1 9 c.1091C>G p.T364R Pulkkinen et al., 2001 3 9 c.1132C>T p.Q378X Pulkkinen et al., 2001; Cai et al., 2001 1 10 c.1318T>G p.C440G Present study 1 10 c.1233T>G p.N411K Le Saux et al., 2001 7 12 c.1552C>T p.R518X Meloni et al., 2001; Chassaing et al., 2004 3 12 c.1553G>A p.R518Q Le Saux et al., 2001; Chassaing et al., 2004 1 14 c.1798C>T p.R600G Present study 1 17 c.2248-2_2248- 1del - Present study 1 19 c.2428G>A p.V810M Present study 1 19 c.2458G>C p.A820P Present study 3 23 c.3088C>T p.R1030X Le Saux et al., 2001 1 24 c.3340C>T p.R1114C Present study 1 24 c.3380C>T p.M1127T Present study 1 24 c.3389C>T p.T1130M Chassaing et al., 2004; Gotting et al., 2004 1 24 c.3413G>A p.R1138Q Le Saux et al., 2000; Ringpfeil et al., 2000; Le Saux et al., 2001 13 24 c.3421C>T p.R1141X Bergen et al., 2000; Germain et al., 2000; Ringpfeil et al., 2000; Le Saux et al., 2001; Pulkkinen et al., 2001; Uitto et al., 2001; Hu et al., 2003 ; Gotting et al., 2004 1 25 c.3544_3544dupC p.L1182PfsX96 Present study 2 26 c.3736-1G>A - Ringpfeil et al., 2000; Le Saux et al., 2001 1 27 c.3823C>T p.R1275X Present study 2 28 c.4015C>T p.R1339C Le Saux et al., 2001 1 28 c.4036C>T p.P1346S Present study 2 29 c.4198G>A p.E1400K Chassaing et al., 2004 1 30 c.4318_4318delA p.M1440CfsX24 Present study The number of families in which a specific mutation was found (in heterozygous and in homozygous state) is reported. Login to comment 75 ABCC6 p.Arg1141* In the PXE patients examined, exon 24 of the ABCC6 gene was the most affected one, and c.3421C>T (p.R1141X) was the most frequent mutation, being homozygous in 7 of 38 families (18.4%), and heterozygous in another 6 unrelated families (15.8%), including the 2 families (3 patients) in whom it was the only detected mutation. Login to comment 76 ABCC6 p.Arg1141* Therefore, the p.R1141X mutation was present in 26.3% of all the alleles examined (20/76). Login to comment 77 ABCC6 p.Arg1138Gln ABCC6 p.Thr1130Met ABCC6 p.Arg1114Cys ABCC6 p.Met1127Thr Exon 24 was affected by other types of mutations [c.3340C>T (p.R1114C), c.3380C>T (p.M1127T), c.3389C>T (p.T1130M), c.3413G>A (R1138Q)] in four families, for a total of 17 out of 38 families (44.7%) and for a total of 24 alleles over the 76 examined (31.6%). Login to comment 79 ABCC6 p.Gln378* In exon 9, c.1132C>T (p.Q378X) mutation was found in homozygosity in two families and in compound heterozygous in one family. Login to comment 80 ABCC6 p.Arg518Gln ABCC6 p.Arg518* In exon 12, mutation c.1552C>T (p.R518X) was homozygous in two families and heterozygous in other 5 families, and mutation c.1553G>A (p.R518Q) was heterozygous in 3 unrelated families. Login to comment 81 ABCC6 p.Arg1141* ABCC6 p.Arg518* ABCC6 p.Gln378* In order to identify a possible founder origin of recurrent disease-associated alleles, a limited haplotype analysis was performed in 11 unrelated families carrying the same mutation (p.Q378X, p.R518X, p.R1141X) in homozygous state (data not shown). Login to comment 82 ABCC6 p.Gln378* The analysis of the two families with the p.Q378X mutation revealed different alleles, identical-by-state. Login to comment 83 ABCC6 p.Arg518* The analysis of the two families with the p.R518X mutation revealed common haplotypes, suggesting a possible consanguinity. Login to comment 84 ABCC6 p.Arg1141* The analysis of the seven families with the p.R1141X mutated allele showed common haplotypes, suggesting the presence of a common ancestor. Login to comment 85 ABCC6 p.Arg1141* Comparison of the analysis of 9 intragenic single-nucleotide polymorphisms, evaluated in Italian as well as in French patients (Chassaing et al., 2004), showed identical alleles, suggestive for a founder origin of p.R1141X mutation in European PXE patients. Login to comment 86 ABCC6 p.Arg518* The same comparison, in the case of p.R518X mutation, revealed different alleles, between Italian and French patients, identical-by state. Login to comment 97 ABCC6 p.Val810Met ABCC6 p.Cys440Gly ABCC6 p.Arg1114Cys ABCC6 p.Pro1346Ser ABCC6 p.Met1127Thr ABCC6 p.Ala820Pro ABCC6 p.Arg600Gly The majority of missense mutations would probably result in alterations of the MRP6 conformation [c.1318T>G (p.C440G), c.1798C>T (p.R600G), c.2428G>A (p.V810M), c.2458G>C (p.A820P), c.3340C>T (p.R1114C), c.3380C>T (p.M1127T)], whereas c.4036C>T (p.P1346S) mutation would probably cause a loss of function of MRP6, since previous studies have shown that missense mutations located in the second NBF (Nucleotyde Binding Fold) of MRP6 are able to completely abolish the transport activity of the protein (Ilias et al., 2002). Login to comment 99 ABCC6 p.Cys440Gly ABCC6 p.Met1127Thr ABCC6 p.Met1127Thr All but one mutation (p.M1127T) involve residues highly conserved in the MRP6 protein among different species (Mus musculus; Rattus norvegicus) and all but two mutations (p.C440G; p.M1127T) involve residues rather conserved in the C subfamily of ABC membrane transporters. Login to comment 100 ABCC6 p.Arg1275* The nonsense mutation [c.3823C>T (p.R1275X)] and the two frameshift mutations [c.3544_3544dupC (p.L1182PfsX96), c.4318_4318delA (p.M1440CfsX24)] are predicted to result in the production of a truncated protein. Login to comment 111 ABCC6 p.Arg1141* In particular, by considering patients homozygous for the most recurrent p.R1141X mutation, that is associated with the almost complete absence of MRP6 (Le Saux et al., 2001; Hu et al., 2003), the correlation between total clinical score and age was highly consistent (p<0.01). Login to comment 118 ABCC6 p.Arg1141* ABCC6 p.Arg518Gln ABCC6 p.Arg518* ABCC6 p.Gln378* Some were recurrent mutations (p.Q378X, p.R518X, p.R518Q, p.R1141X), however the majority of mutations were sporadic variants. Login to comment 119 ABCC6 p.Arg1141* The most frequent p.R1141X PXE-related allele shared a common haplotype identical-by-descent in seven Italian families homozygous for this mutation. Login to comment 128 ABCC6 p.Arg1141* As a further example, patient I- 3055-001, who was also a strong smoker, was the only PXE patient homozygous for the p.R1141X mutation with heart and gastro-intestinal alterations, whereas her sister had only eye and skin lesions, underlining the importance of exogenous factors that may interfere with elastin deposition and degradation. Login to comment 134 ABCC6 p.Arg1268Gln Interestingly, it has been observed that a particular ABCC6/MRP6 polymorphism, called c.3803G>A (p.R1268Q), is associated with reduced amount of plasma triglycerides and higher plasma HDL cholesterol (Wang et al., 2001). Login to comment