ABCMdb

ABCD1 p.Tyr547Cys

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Publications

PMID: 23300730 [PubMed] Amorosi CA et al: "X-linked adrenoleukodystrophy: molecular and functional analysis of the ABCD1 gene in Argentinean patients."

No. Sentence Comment

5 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). Login to comment
66 AMN 2 Phenotype 1 cDNA mutation Protein level Exon/Intron Polymorphisms Exon/Intron Protein level 1 AMN c.2006A.G p.His669Arg 10 c.55G.T 1 p.Ala19Ser c.1992-32C.T 9 2 CCALD c.1137dupC p.Glu380Argfs*21 3 c.1992-32C.T 9 c.2019C.T 10 p.Phe673Phe 3 AO c.1022C.A p.Ala341Asp 2 c.1634+14T.A 6 c.1992-32C.T 9 4 AO c.1081+5G.C Splice mutation c.1548G.A 6 p.Leu516Leu r.907_1494del p.Leu303_Glu498 IVS2 c.1992-32C.T 9 5 Asymptomatic c.1640A.G p.Tyr547Cys 7 6 CCALD c.1714_1725dek12bp p.Ser572_Asp575del 7 7 Adolescent cerebral ALD c.761delC p.Thr254Argfs*82 1 c.1634+14T.A 6 8 -- c.1259A.C p.His420Pro 1 9 AMN c.2006A.G p.His669Arg 10 c.1992-32C.T 9 10 CCALD c.852_853insACTC p.Ser284fs*16 1 1 Nucleotides numbered reflects cDNA numbering with +1 corresponding to the A of the ATG initiation codon in the reference sequence (NM000033), according to journal guidelines (www.hgvs.org/mutnomen). 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
88 These new changes included 3 frameshifts (p.Ser284fs*16; p.Glu380Argfs*21; p.Thr254Argfs*82); a deletion (p.Ser572_Asp575del), a splicing mutation (c.1081+5G.C) and three single base pair substitutions (p.Ala341Asp, p.His420Pro and p.Tyr547Cys). Login to comment
94 It was verified by functional studies that the missense substitutions p.Ala341Asp, p.His420Pro and p.Tyr547Cys are disease-causing mutations. Login to comment
95 When the construct encoding a substitution p.Tyr547Cys was transfected into X-ALD fibroblasts, ALDP was not detected by western blot analysis (Figure 1) and peroxisomal b-oxidation was deficient (Figure 2). Login to comment
101 PolyPhen predicted that p.Ala341Asp is possibly damaging, and p.Tyr547Cys and p.His420Pro can be probably damaging (Table 2). 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
139 For the p.Ala341Asp, p.Tyr547Cys and p.His420Pro alleles, we did not observe protein in western blots and the level of b-oxidation was deficient (Figures 1, 2, 3, 4 and data not shown). Login to comment
140 These results confirm that p.Ala341Asp, p.Tyr547Cys and p.His420Pro are the causing disease mutations in each patient. 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