ABCMdb

PMID: 15723264

Hendig D, Schulz V, Eichgrun J, Szliska C, Gotting C, Kleesiek K
New ABCC6 gene mutations in German pseudoxanthoma elasticum patients.
J Mol Med (Berl). 2005 Feb;83(2):140-7. Epub 2004 Nov 10., [PubMed]

Sentences

No. Mutations Sentence Comment

35 ABCC6 p.Arg1141* The most frequent mutation in PXE patients of European descent is the nonsense mutation p.R1141X [15, 18, 19]. Login to comment 74 ABCC6 p.Arg1141* In addition, the presence of the frequent c.3421C>T (p.R1141X) mutation was analyzed in all patients and relatives as previously reported by us [18]. Login to comment 75 ABCC6 p.Arg1141* The nonsense mutation p.R1141X was the most frequent mutation found in the panel of PXE patients investigated in the present study. Login to comment 77 ABCC6 p.Arg1141* Heterozygous carriers but no homozygous carriers of the p.R1141X mutation were identified among the 54 unaffected relatives (data not shown). Login to comment 78 ABCC6 p.Arg1141* One heterozygous carrier of the nonsense mutation p.R1141X was detected among 910 healthy Westphalian blood donors. Login to comment 83 ABCC6 p.Met751Lys ABCC6 p.Arg760Trp ABCC6 p.Leu851Pro ABCC6 p.Phe952Cys ABCC6 p.Ser1403Arg Among these, five were missense mutations (p.M751K, p.R760W, p.L851P, p.F952C, and p.S1403R), one was a single base pair deletion (c.4434delA) and one a larger out-of-frame deletion (c.2835_2850del16). Login to comment 86 ABCC6 p.Ser1403Arg The second novel missense mutation c.4209C>A (p.S1403R) was identified in one allele of a male PXE patient. Login to comment 87 ABCC6 p.Arg760Trp ABCC6 p.Ser1403Arg An alignment of the human MRP proteins using the ClustalW program identified the mutations p.R760W and p.S1403R to alter amino acid residues, which are highly conserved in the human MRP proteins (data not shown). Login to comment 89 ABCC6 p.Met751Lys Furthermore, five PXE patients were heterozygous for the fourth novel missense mutation c.2252T>A, which resulted in a substitution of methionine to lysine in position 751 of the amino acid sequence of MRP6. Login to comment 90 ABCC6 p.Met751Lys ABCC6 p.Leu851Pro The mutations p.M751K and p.L851P affect amino acid residues which are not conserved between the human MRP proteins, but which cosegregate with a PXE phenotype in five families and were not present in a cohort of 200 alleles of healthy controls (Table 2). Login to comment 93 ABCC6 p.Phe952Cys Sequence analysis showed that the missense mutation p.F952C is located in cis-position to the deletion c.2835_2850del16 (Fig. 2). Login to comment 94 ABCC6 p.Arg765Gln ABCC6 p.Leu946Ile Performing DHPLC and sequence analysis we also detected four different ABCC6 mutations (c.1995delG, p.R765Q, c.2787+1G>T, and p.L946I) which had already been categorized as PXE-causing mutations by other groups (Table 2) [9, 19, 20, 22]. Login to comment 96 ABCC6 p.Arg765Gln The missense mutation p.R765Q and the splice site mutation c.2787+1G>T were also observed in a heterozygous state in five unaffected or not yet affected relatives of the PXE patients (Table 2). Login to comment 97 ABCC6 p.Leu946Ile Seven healthy control individuals were heterozygous for the missense mutation p.L946I, which was novel at the time of investigation. Login to comment 104 ABCC6 p.Arg1141* The nonsense mutation p.R1141X, which was identified in 34 (44.7%) PXE patients, was the most frequent mutation in our cohort of German PXE patients. Login to comment 107 ABCC6 p.Arg1141* In contrast to the p.R1141X mutation, most of these variations were unique in the cohort studied. Login to comment 114 ABCC6 p.Met751Lys ABCC6 p.Arg760Trp ABCC6 p.Leu851Pro ABCC6 p.Phe952Cys ABCC6 p.Ser1403Arg Four of these had been described elsewhere [9, 19, 22] and seven were novel, namely the missense mutations p.M751K, p.R760W, p.L851P, p.F952C, and p.S1403R and the deletions c.2835_2850del16 and c.4434delA. Login to comment 115 ABCC6 p.Arg760Trp ABCC6 p.Ser1403Arg The mutations p.R760W and p.S1403R alter amino acid residues, which are highly conserved in the human MRP proteins and were not found among healthy relatives and control individuals. Login to comment 116 ABCC6 p.Ser1403Arg The mutation p.S1403R affects a highly conserved amino acid residue in the ABC signature (LSVGQK) of NBF2. Login to comment 118 ABCC6 p.Met751Lys ABCC6 p.Leu851Pro ABCC6 p.Phe952Cys The mutations p.M751K, p.L851P, and p.F952C are located in the NBF1 and affect amino acid residues which are not conserved in the human, but highly conserved between human, mouse, and rat MRP6 proteins. Login to comment 119 ABCC6 p.Met751Lys The mutation p.M751K affects a residue immediately preceding the ABC signature of the NBF1, which is predicted to be critical for the function of MRP6 as a transmembrane protein and for the recognition, binding, and hydrolysis of ATP [10, 32]. Login to comment 124 ABCC6 p.Met751Lys ABCC6 p.Leu851Pro ABCC6 p.Phe952Cys The mutations p.M751K, p.L851P, and p.F952C were also absent in 100 healthy blood donors. Login to comment 126 ABCC6 p.Phe952Cys Furthermore, we detected the missense mutation p.F952C to occur on the same allele as the deletion c.2835_2850del16. Login to comment 127 ABCC6 p.Phe952Cys Subsequently the novel p.F952C mutation did not play a role in the manifestation of PXE in the case of the 47-year-old PXE patient. Login to comment 131 ABCC6 p.Leu946Ile ABCC6 p.Leu946Ile Morcher et al. [22] considered the missense mutation p.L946I causative for a manifestation of PXE. This observation is not in accordance with the data that we obtained from a control cohort of 100 healthy Westphalian blood donors to investigate the role of p.L946I in PXE. Login to comment 132 ABCC6 p.Leu946Ile ABCC6 p.Leu946Ile The appearance of p.L946I in the general population sheds doubt on the view that p.L946I is a disease-causing mutation but rather a polymorphism. Login to comment 133 ABCC6 p.Leu946Ile However, we cannot rule out the possibility that p.L946I has a phenotypic effect in a compound heterozygote with a severe mutation on the other allele. Login to comment 134 ABCC6 p.Arg1141* ABCC6 p.Arg1268Gln ABCC6 p.Met751Lys ABCC6 p.Arg760Trp ABCC6 p.Leu851Pro ABCC6 p.Ser1403Arg All but two of the PXE patients who were identified to be heterozygous carriers of the six novel mutations (p.M751K, p.R760W, p.L851P, p.S1403R, and c.2835_ 2850del16) were also found to carry one other PXE-causing ABCC6 mutation (c.2787+1G>T, p.R1141X, c.3736-1G>A, p.R1268Q). Login to comment 136 ABCC6 p.Arg760Trp In this family a 35-year-old woman suffering from PXE was identified to be a compound heterozygote for p.R760W and c.2787+1G>T. Login to comment 143 ABCC6 p.Met751Lys ABCC6 p.Arg760Trp ABCC6 p.Leu851Pro ABCC6 p.Ser1403Arg In conclusion, we suggest six mutations, namely the mutations p.M751K, p.R760W, p.L851P, p.S1403R, c.2835_2850del16, and c.4434delA to induce a dysfunctional or truncated MRP6 protein resulting in a manifestation of PXE. Login to comment 180 ABCC6 p.Gln378* ABCC6 p.Gln378* Cai L, Lumsden A, Guenther UP, Neldner SA, Zäch S, Knoblauch H, Ramesar R, Hohl D, Callen DF, Neldner KH, Lindpaintner K, Richards RI, Struk B (2001) A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum. J Mol Med 79:536-546 17. Login to comment 181 ABCC6 p.Arg1268Gln Germain DP, Perdu J, Remones V, Jeunemaitre X (2000) Homozygosity for the R1268Q mutation in MRP6, the pseudoxanthoma elasticum gene, is not disease-causing. Login to comment