ABCC6 p.Arg1141Cys
| ClinVar: |
c.3421C>T
,
p.Arg1141*
D
, Pathogenic
|
| LOVD-ABCC6: |
p.Arg1141*
D
|
| Predicted by SNAP2: | A: N (72%), C: N (82%), D: N (53%), E: N (61%), F: D (71%), G: N (87%), H: N (87%), I: N (57%), K: N (93%), L: N (57%), M: N (57%), N: N (82%), P: D (63%), Q: N (93%), S: N (87%), T: N (78%), V: N (57%), W: D (80%), Y: D (66%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: N, N: N, P: N, Q: N, S: N, T: N, V: D, W: D, Y: D, |
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[hide] Premature termination codon read-through in the AB... J Invest Dermatol. 2013 Dec;133(12):2672-7. doi: 10.1038/jid.2013.234. Epub 2013 May 23. Zhou Y, Jiang Q, Takahagi S, Shao C, Uitto J
Premature termination codon read-through in the ABCC6 gene: potential treatment for pseudoxanthoma elasticum.
J Invest Dermatol. 2013 Dec;133(12):2672-7. doi: 10.1038/jid.2013.234. Epub 2013 May 23., [PMID:23702584]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder manifesting with ectopic connective tissue mineralization, caused by mutations in the ABCC6 gene, with ~35% of all mutations being premature termination mutations. In this study, we investigated the therapeutic potential of the nonsense codon read-through-inducing drug, PTC124, in treating PXE. The ability of this drug to facilitate read-through of nonsense mutations was examined in HEK293 cells transfected with human ABCC6 expression constructs harboring seven different PXE-associated nonsense mutations, and was evaluated by immunofluorescence and In-Cell ELISA. Our data demonstrated that PTC124 did not exhibit cytotoxicity in concentrations up to 20 mug ml(-1), and the facilitated read-through varied not only with dose but also with sequence context. Considering the redundancy of the genetic code, it was postulated that in case of the most common recurrent nonsense mutation, p.R1141X, the read-through may result in substitution of the arginine 1,141 by glycine, tryptophan, or cysteine. Their potential pathogenicity was tested in a recently developed zebrafish messenger RNA (mRNA) rescue assay, and demonstrated that all three mRNA transcripts were able to rescue abcc6a morpholino-induced phenotype of zebrafish. Thus, our results suggest that read-through of nonsense mutations in ABCC6 by PTC124 may have potential for pharmacologic treatment of PXE.
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No. Sentence Comment
132 Capped full-length human ABCC6 mRNA corresponding to wild-type, R1141X, or putative read-through substitutions of arginine1141 by cysteine, tryptophan, or glycine was transcribed from an expression vector pCMV-Tag4B using the T3 mMessage mMachine kit (Ambion, Austin, TX).
X
ABCC6 p.Arg1141Cys 23702584:132:114
status: NEW