ABCMdb

PMID: 16835894

Schulz V, Hendig D, Henjakovic M, Szliska C, Kleesiek K, Gotting C
Mutational analysis of the ABCC6 gene and the proximal ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE).
Hum Mutat. 2006 Aug;27(8):831., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCC6 p.Arg1141* Frequent alterations were the PXE-mutations p.R1141X, Ex23,_Ex29del, and c.2787+1G>T. Login to comment 72 ABCC6 p.Arg1141* The most common PXE mutations were the nonsense mutation p.R1141X, the splice site mutation c.2787+1G>T and the large deletion Ex23_Ex29del. Login to comment 82 ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg1138Trp ABCC6 p.Arg1314Trp ABCC6 p.Arg518* ABCC6 p.Gln378* ABCC6 p.Arg765Gln ABCC6 p.Thr1301Ile ABCC6 p.Arg1314Gln ABCC6 p.Trp1241Cys ABCC6 p.Asn497Lys ABCC6 p.Thr1130Met ABCC6 p.Arg1114His ABCC6 p.Arg391Gly ABCC6 p.Met751Lys ABCC6 p.Arg1114Cys ABCC6 p.Arg760Trp ABCC6 p.Leu851Pro ABCC6 p.Phe952Cys ABCC6 p.Ser1403Arg ABCC6 p.Gly1311Glu ABCC6 p.Tyr1239His ABCC6 p.Val415Ala ABCC6 p.Trp38Ser ABCC6 p.Leu1063Arg ABCC6 p.Ser1049Ala ABCC6 p.Arg487Gln ABCC6 p.Leu252Phe Summary of ABCC6/MRP6 mutations identified in German PXE patients Change in Number of Allelic frequency Exona nucleotideb Amino acid Statusc families in blood donorsd Referenceg i-1e c.37-1G>Af altered splicing hm 1 0 / 200 This study 2 c.113G>C p.W38S ht 1 0 / 200 This study i-3 c.346-6G>A altered splicing ht 2 Nd A, B 7 c.754C>T p.L252F ht 1 0 / 200 This study 9 c.1132C>T p.Q378X ht 4 Nd B, C 9 c.1171A>G p.R391G ht 1 Nd B, D 10 c.1244T>C p.V415A ht 1 0 / 200 This study 12 c.1460G>A p.R487Q ht 1 0 / 200 This study 12 c.1491C>A p.N497K ht 1 0 / 200 This study 12 c.1552C>T p.R518X ht 1 Nd B, E i-12 c.1574_1575insG p.L525fsX73 ht 1 0 / 200 This study 16 c.1995delG p.A667fsX20 ht 3 Nd A, F, G 18 c.2252T>A p.M751K ht 3 Nd F, G 18 c.2278C>T p.R760W ht 2 Nd B, F, G Change in Number of Allelic frequency Exona nucleotideb Amino acid Statusc families in blood donorsd Referenceg 18 c.2294G>A p.R765Q ht 2 Nd A, F, G, H 19 c.2552T>C p.L851P ht 1 Nd F i-21 c.2787+1G>T altered splicing ht 7 Nd B, C, F, I, J 22 c.2835_2850del16 p.P946fsX17 ht 1 Nd F 22 c.2855T>G p.F952C ht 1 Nd F 23 c.3145T>G p.S1049A ht 1 0 / 200 This study 23 c.3188T>G p.L1063R ht 1 0 / 200 This study 24 c.3340C>T p.R1114C ht 1 Nd B, K, G, L 24 c.3341G>A p.R1114H ht 1 Nd G, H, L, M 24 c.3389C>T p.T1130M ht 1 Nd B, D, G, H, K, L, M, N 24 c.3413G>A p.R1138Q ht 1 Nd A, B, D, J, K, L, N 24 c.3412C>T p.R1138W ht 1 Nd N 24 c.3421C>T p.R1141X hm, ht 26 Nd B, G, J, K, L, M, N, O, P, Q, R, S i-24 c.3505_3506+2delA GGT altered splicing ht 1 0 / 200 This study i-24 c.3507-3C>T altered splicing ht 2 Nd B 26 c.3715T>C p.Y1239H ht 1 Nd L 26 c.3723G>C p.W1241C ht 1 Nd A, L i-26 c.3736-1G>A altered splicing ht 1 Nd B, L, N 27 c.3775delT p.W1259fsX13 ht 1 Nd B, J, L, O i-27 c.3883-6G>A altered splicing ht 1 Nd B 28 c.3902C>T p.T1301I ht 1 Nd A, G, L 28 c.3932G>A p.G1311E ht 1 Nd L 28 c.3940C>T p.R1314W ht 1 Nd A, G, L 28 c.3941G>A p.R1314Q ht 1 Nd A, B, G, L 29 c.4182delG p.N1394fsX8 ht 2 Nd G, H, L 30 c.4209C>A p.S1403R ht 1 Nd F 31 c.4434delA p.R1479fsX25 hm 1 Nd F 23-29 Ex23_Ex29del p.A999_S1403del ht 5 Nd A, B, D, E, G, H, O, R a The exon that contains the ABCC6 sequence variation. Login to comment 89 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.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg1138Gln ABCC6 p.Arg1138Trp ABCC6 p.Arg1138Trp ABCC6 p.Arg1314Trp ABCC6 p.Arg518* ABCC6 p.Arg518* ABCC6 p.Gln378* ABCC6 p.Gln378* ABCC6 p.Gln378* ABCC6 p.Gln378* ABCC6 p.Arg765Gln ABCC6 p.Arg765Gln ABCC6 p.Arg765Gln ABCC6 p.Thr1301Ile ABCC6 p.Arg1314Gln ABCC6 p.Trp1241Cys ABCC6 p.Asn497Lys ABCC6 p.Thr1130Met ABCC6 p.Arg1114His ABCC6 p.Arg391Gly ABCC6 p.Arg391Gly ABCC6 p.Met751Lys ABCC6 p.Met751Lys ABCC6 p.Met751Lys ABCC6 p.Arg1114Cys ABCC6 p.Arg760Trp ABCC6 p.Arg760Trp ABCC6 p.Leu851Pro ABCC6 p.Phe952Cys ABCC6 p.Ser1403Arg ABCC6 p.Gly1311Glu ABCC6 p.Tyr1239His ABCC6 p.Val415Ala ABCC6 p.Val415Ala ABCC6 p.Trp38Ser ABCC6 p.Leu1063Arg ABCC6 p.Ser1049Ala ABCC6 p.Arg487Gln ABCC6 p.Leu252Phe ABCC6 p.Leu252Phe Genotypes and phenotypes of the PXE patients analyzed in this study Phenotype Genotypeb No.a Sex, Age Age on diagnosis Organ involvement Mutations 1 M 36 11 E, S, G p.R1141X p.R1141X 2 F 44 39 E, S, G, A p.R1141X Ex23_Ex29del 3 F 41 7 E, S p.R1141X p.R1141X 4 F 46 19 E, S, A p.R1141X p.R1141X 5 F 59 55 E, S, A c.37-1G>A c.37-1G>A 6c F 63 16 E, S, H, V, A Ex23_Ex29del c.4182delG 7 F 24 15 E, S c.4434delA c.4434delA 8 M 60 23 E, S p.Q378X p.R1141X 9 F 79 65 E, S, A c.2787+1G>T p.R1141X 10 F 55 35 E, S, G, H, V, A p.Q378X c.2787+1G>T 11 F 47 14 S c.1995delG c.2787+1G>T 12c F 36 24 E, S c.2787+1G>T c.4182delG 13 F 56 8 E, S p.R1141X c.3507-3C>T 14 M 72 55 E, S, H, V p.R1141X 15 F 69 51 E, S c.1995delG p.R765Q 16 F 19 11 S p.R760W p.R1141X 17c F 59 50 E, S, H, V, A p.R1141X p.G1311E 18c M 54 32 E, S p.R1141X p.Y1239H 19-1 M 63 53 E, H p.L252F p.V415A p.R765Q 19-2 F 58 48 E, S p.L252F p.V415A p.R765Q 20 M 54 44 E, S, V, A c.3775delT c.346-6G>A 21 M 52 43 E, S, A p.R1141X c.3883-6G>A 22-1 M 47 36 E, S, G, H, V p.R518X 22-2 M 45 34 E, S, H p.R518X 23 F 35 22 E, S, A p.W38S 24 F 40 30 E c.346-6G>A 25-1 M 58 46 E, S, A p.R1141X c.3883-6G>A 25-2 M 19 10 S p.R1141X c.3883-6G>A 26-1 F 46 18 E, S, V p.R487Q c.3883-6G>A 27c F 62 30 E, S, A p.Q378X p.R1114H 28 F 59 49 E, A p.R1314Q c.3507-3C>T 29c F 30 10 E, S c.1995delG p.R1114C 30 M 67 52 E p.L1063R p.R1141X 31 F 50 46 E, S, V p.M751K p.R1141X 32 F 27 24 S Ex23_Ex29del 33c F 34 19 E, S Ex23_Ex29del p.T1130M 34 F 33 19 E, S c.2787+1G>T p.W1241C 35 M 47 15 E, S, G, H, V, A Ex23_Ex29del 36 M 72 63 E, S p.S1049A c.3736-1G>A p.S1403R 37 F 34 16 E, S c.2787+1G>T 38 F 42 8 E, S, V p.R1141X p.R1314W 39 F 37 20 E, S p.N497K 40 F 54 33 E, S, V, A p.M751K p.R1141X 41 M 53 49 E, S, G, H, V p.R1141X 42-1 F 52 38 E, S p.R391G p.R1141X 42-2 F 43 28 E, S p.R391G p.R1141X 43 F 64 58 S, A 44-1 F 51 27 E, S, A p.R1141X 44-2 F 18 9 E, S 44-3 F 54 26 E, S, V, A p.R1141X 45-1 F 64 49 E, S, G, V p.R1138Q 45-2 F 62 48 E, S, A p.R1138Q 46 M 56 25 E, S, V p.R1141X p.T1301I 47 F 34 23 E, S p.R760W c.2787+1G>T 48 M 47 24 E, S, V, A c.2835_2850del16 p.F952C p.R1141X 49 F 28 11 E, S, G, V p.M751K p.R1141X 50 F 39 25 E, S, V p.L851P p.R1141X c.3505_3506+2 delAGGT 51 F 61 16 E, S, H, A p.Q378X p.R1141X 52-1 F 40 20 E, S p.R1138W p.R1141X 52-2 F 43 23 E, S p.R1138W p.R1141X 53 M 68 66 E, H, V, G, A c.1574_1575insG p.R1141X F = female, M = male, wt = wild-type, hm = homozygote, ht = heterozygote, cht = compound heterozygote, nd = not determined, MSM = microsatellite marker, E = eyes, S = skin, G = gastrointestinum, H = heart, V = vascular tissue and A = arterial hypertension. Login to comment 93 ABCC6 p.Asn497Lys ABCC6 p.Val415Ala ABCC6 p.Trp38Ser ABCC6 p.Leu1063Arg ABCC6 p.Ser1049Ala ABCC6 p.Arg487Gln ABCC6 p.Leu252Phe Novel PXE mutations Among the 42 different ABCC6 mutations detected in our PXE cohort, 32 had been described elsewhere (Bergen et al., 2000; Germain et al., 2000; Ringpfeil et al., 2000; Struk et al., 2000; Cai et al., 2001; Le Saux et al., 2001; Pulkkinen et al., 2001; Hu et al., 2003; Chassaing et al., 2004; Gheduzzi et al., 2004; Götting et al., 2004; Hendig et al., 2005; Schulz et al., 2005a; Schulz et al., 2005b), and 10 were novel DNA variations, namely c.37-1G>A, p.W38S, p.L252F, p.V415A, p.R487Q, p.N497K, c.1574_1575insG, p.S1049A, p.L1063R and c.3505_3506+2delAGGT. Login to comment 96 ABCC6 p.Asn497Lys ABCC6 p.Trp38Ser The splice site mutation c.37-1G>A occurred in a homozygous form in one PXE patient and the missense mutations p.W38S and p.N497K were found in a heterozygous state in 2 patients where no further PXE mutations could be identified (Table 2). Login to comment 97 ABCC6 p.Arg1141* ABCC6 p.Arg765Gln ABCC6 p.Leu851Pro ABCC6 p.Ser1403Arg ABCC6 p.Val415Ala ABCC6 p.Leu1063Arg ABCC6 p.Ser1049Ala ABCC6 p.Arg487Gln ABCC6 p.Leu252Phe The other 7 PXE patients were compound heterozygous for the novel DNA variations p.L252F, p.V415A, p.R487Q, p.S1049A, p.L1063R, c.1574_1575insG and c.3505_3506+2delAGGT, as well as for the known PXE-causing mutations p.R765Q, p.R1141X, p.L851P, c.3736-1G>A and p.S1403R (Bergen et al., 2000; Germain et al., 2000; Ringpfeil et al., 2000; Struk et al., 2000; Le Saux et al., 2001; Uitto et al., 2001; Hendig et al., 2005). Login to comment 102 ABCC6 p.Asn497Lys ABCC6 p.Val415Ala ABCC6 p.Trp38Ser ABCC6 p.Leu1063Arg ABCC6 p.Ser1049Ala ABCC6 p.Arg487Gln ABCC6 p.Leu252Phe The positions of the novel mutations c.37-1G>A, p.W38S, p.L252F, p.V415A, p.R487Q, p.N497K, c.1574_1575insG, p.S1049A, p.L1063R, and c.3505_3506+2delAGGT are indicated. Login to comment 123 ABCC6 p.Arg1141* The frequencies of these mutations were similar to those reported in previous European studies, in which the nonsense mutation p.R1141X and the large deletion Ex23_Ex29del were described as frequent ABCC6 mutations in French, Italian and Dutch PXE patients and most of the further ABCC6 alterations were determined as unique mutations (Chassaing et al., 2004; Gheduzzi et al., 2004; Hu et al., 2004). Login to comment 125 ABCC6 p.Arg518Gln ABCC6 p.Arg518* The disease-causing mutations p.R518Q and p.R518X that were frequently found in French, Italian and Swiss PXE patients (Chassaing et al., 2004; Gheduzzi et al., 2004; Miksch et al., 2005), rarely occurred in our PXE cohort and were not found in PXE families of Dutch origin (Hu et al., 2004). Login to comment 150 ABCC6 p.Leu1063Arg ABCC6 p.Arg487Gln Unfortunately, DNA samples from first-degree relatives of those PXE patients carrying the new mutations were only available from those 3 patients who harbored the novel mutations p.R487Q, p.L1063R, c.3505_3506del+2AGGT. Login to comment 152 ABCC6 p.Arg1141* ABCC6 p.Leu1063Arg For the p.L1063R variant that was found in a compound heterozygous state with the nonsense mutation p.R1141X, segregation with the PXE phenotype within the patient's family was observed (Table 2). Login to comment 153 ABCC6 p.Arg487Gln The p.R487Q variant occurred in compound heterozygous state with the splice site mutation c.3883-6G>A and segregated with the PXE diagnosis in that family (Figure 3). Login to comment 155 ABCC6 p.Val415Ala ABCC6 p.Ser1049Ala ABCC6 p.Leu252Phe In the 4 patients carrying the new mutations p.L252F, p.V415A, p.S1049A and c.3505_3506+2delAGGT we found a total of 3 compound heterozygous mutations in each patient (Table 2). Login to comment 157 ABCC6 p.Val415Ala ABCC6 p.Ser1049Ala ABCC6 p.Leu252Phe Therefore, the pathogenic influence of the novel mutations p.L252F, p.V415A and p.S1049A is difficult to predict. Login to comment 158 ABCC6 p.Ser1403Arg ABCC6 p.Val415Ala ABCC6 p.Ser1049Ala ABCC6 p.Leu252Phe However, the assumption that these mutations are disease-causing is supported by the hypothesis that the missense variants p.L252F and p.V415A (Table 2: Patients 19-1 and 19-2), as well as the mutations p.S1049A and p.S1403R (Table 2: Patient 36), might be located in closed proximity in the native MRP6 and therefore the resulting amino acid variants are thought to interfere with each other. Login to comment 162 ABCC6 p.Arg1141* ABCC6 p.Arg487Gln The mutations p.R1141X, which is found in 2 apparently non-consanguineous parts of the family, p.R487Q and c.3883-6G>A could be located. Login to comment 165 ABCC6 p.Arg1141* The index patient and her sister were heterozygous for p.R1141X, but no mutation could be detected in the ABCC6 gene of the daughter. Login to comment 183 ABCC6 p.Arg1268Gln This assumption is confirmed by the fact that an association of the polymorphism p.R1268Q in the exon 27 of the ABCC6 gene with plasma lipoprotein levels has already been observed (Wang et al., 2001). Login to comment