ABCMdb

ABCD1 p.Ala19Ser

Predicted by SNAP2:	C: N (87%), D: D (71%), E: N (53%), F: D (63%), G: N (53%), H: D (66%), I: N (93%), K: N (57%), L: N (87%), M: N (78%), N: D (59%), P: N (66%), Q: D (59%), R: D (66%), S: N (87%), T: N (87%), V: N (97%), W: D (75%), Y: D (66%),
Predicted by PROVEAN:	C: N, D: D, E: N, F: N, G: N, H: D, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N,

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Publications
[hide] X-linked adrenoleukodystrophy: molecular and funct... PLoS One. 2012;7(12):e52635. doi: 10.1371/journal.pone.0052635. Epub 2012 Dec 31. Amorosi CA, Myskova H, Monti MR, Argarana CE, Morita M, Kemp S, Dodelson de Kremer R, Dvorakova L, Oller de Ramirez AM
X-linked adrenoleukodystrophy: molecular and functional analysis of the ABCD1 gene in Argentinean patients.
PLoS One. 2012;7(12):e52635. doi: 10.1371/journal.pone.0052635. Epub 2012 Dec 31., [PMID:23300730]

Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disease associated with mutations in the ABCD1 gene that encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long-chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues, due to a defect in peroxisomal VLCFA beta-oxidation. In the present study, we analyzed 10 male patients and 17 female carriers from 10 unrelated pedigrees with X-ALD from Argentina. By sequencing the ABCD1 we detected 9 different mutations, 8 of which were novel. These new mutations were verified by a combination of methods that included both functional (western blot and peroxisomal VLCFA beta-oxidation) and bioinformatics analysis. The spectrum of novel mutations consists of 3 frameshift (p.Ser284fs*16, p.Glu380Argfs*21 and p.Thr254Argfs*82); a deletion (p.Ser572_Asp575del); a splicing mutation (c.1081+5G>C) and 3 missense mutations (p.Ala341Asp, p.His420Pro and p.Tyr547Cys). In one patient 2 changes were found: a known missense (p.His669Arg) and an unpublished amino acid substitution (p.Ala19Ser). In vitro studies suggest that p.Ala19Ser is a polymorphism. Moreover, we identified two novel intronic polymorphisms and two amino acid polymorphisms. In conclusion, this study extends the spectrum of mutation in X-ALD and facilitates the identification of heterozygous females.

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No. Sentence Comment
6 In one patient 2 changes were found: a known missense (p.His669Arg) and an unpublished amino acid substitution (p.Ala19Ser). Login to comment
7 In vitro studies suggest that p.Ala19Ser is a polymorphism. Login to comment
72 Briefly, different degenerate primer pair, introducing point mutation c.55 G.T (p.Ala19Ser), c.1259 A.G (p.His420Pro) or c.1640 A,G (p.Tyr547Cys), were used in a thermal cycling reaction (19 cycles). Login to comment
106 Each line was loaded with the same amount of total protein extracts, as verified with anti-b-actin protein. Line 1: healthy fibroblasts, line 2: X-linked adrenoleukodystrophy fibroblasts, line 3: fibroblats expressing wild type ALDP-GFP, line 4: fibroblats expressing ALDP-GFP (c.55G.T, p.Ala19Ser), line 5: fibroblats expressing ALDP-GFP (c.1640A.G, p.Tyr547Cys). Login to comment
114 In patient 1 (Table 1), we identified two different substitutions, one in exon 1 and other in exon 10 (p.Ala19Ser and p.His669Arg). Login to comment
115 The last one has been identified previously as a disease causing mutation in the X-ALD database (http://www-x-ald.nl), but p.Ala19Ser has not been reported before. Login to comment
116 When a construct carrying substitution p.Ala19Ser was transfected into X-ALD fibroblasts, ALDP was detected by western blot analysis (Figure 1) and peroxisomal b-oxidation was restored to control levels (Figure 2). Login to comment
117 This demonstrates that the p.Ala19Ser may represent a SNP. As expected, SIFT predicted that p.Ala19Ser is tolerated with a score of 0.05 (Table 2). Login to comment
118 PolyPhen predicted that p.Ala19Ser can be a benign variant although the alanine residue at position 19 it was highly conserved between different species (Figure 5). Login to comment
119 Finally, five polymorphisms were detected: 3 novel intronic changes (c.1634+14T.A, c.1992-32C.T and c.55G.T or p.Ala19Ser) and 2 previously reported (c.1548G.A, p.Leu516Leu and c.2019C.T, p.Phe673Phe). Login to comment
150 Missense Change p.Ala19Ser p.Tyr547Cys p.His420Pro p.His669Arg p.Ala341Asp Multiple sequence alignment MSA Highly conserved Highly conserved Relatively conserved Conserved Highly conserved http://www.ebi.ac.uk/clustalw2/ SIFT Tolerated Non-tolerated Tolerated Tolerated Non-tolerated http://blocks.fhcrc.org/sift/SIFT.html PolyPhen Benign Probably damaging Probably damaging Benign Possibly damaging http://genetics.bwh.harvard.edu/pph doi:10.1371/journal.pone.0052635.t002 showed that the mutant transcript is not translated (Figure 3); therefore the levels of b-oxidation are deficient (Figure 4). Login to comment
154 The bioinformatics studies are predictive; however the results were consistent in most cases with functional studies, except for p.Ala19Ser. Login to comment
155 In patient 1 (Table 1) we identified two different one-base substitution, one new in exon 1 (c.55G.T) and one known in exon 10 (c.2006A.G, http://www-x-ald.nl), both of them causing an amino acid change (p.Ala19Ser and p.His669Arg, respectively). Login to comment
156 The p.Ala19Ser allele had similar expression and b-oxidation levels to wild type ALDP in the experiments of transient expression in X-ALD fibroblast (Figures 1 and 2). Login to comment
158 Besides the fact that p.His669Arg has been found as the only mutation in other patients where no protein was detected in western blot also suggests that p.Ala19Ser is a SNP. Login to comment
159 However p.Ala19Ser is highly conserved in all species unlike p.His669 (Figure 6) and both were predicted to be ''bening`` by the Polyphen program and ''tolerated`` by the SIFT program (Table 2). Login to comment