ABCD1 p.His420Pro
| Predicted by SNAP2: | A: N (78%), C: N (72%), D: N (57%), E: N (53%), F: N (72%), G: N (66%), I: N (72%), K: N (57%), L: N (66%), M: N (72%), N: N (78%), P: D (63%), Q: N (61%), R: N (61%), S: N (82%), T: N (78%), V: N (72%), W: N (61%), Y: N (87%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: N, F: N, G: N, I: D, K: N, L: D, M: N, N: N, P: D, Q: N, R: N, S: N, T: N, V: D, W: N, Y: N, |
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[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 In one patient 2 changes were found: a known missense (p.His669Arg) and an unpublished amino acid substitution (p.Ala19Ser).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
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).
X
ABCD1 p.His420Pro 23300730:5:221
status: NEW66 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).
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ABCD1 p.His420Pro 23300730:66:583
status: NEW72 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).
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ABCD1 p.His420Pro 23300730:72:107
status: NEW88 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).
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ABCD1 p.His420Pro 23300730:88:218
status: NEW94 It was verified by functional studies that the missense substitutions p.Ala341Asp, p.His420Pro and p.Tyr547Cys are disease-causing mutations.
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ABCD1 p.His420Pro 23300730:94:85
status: NEW96 Similar results were obtained for the construct containing p.His420Pro substitution (data not show).
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ABCD1 p.His420Pro 23300730:96:61
status: NEW101 PolyPhen predicted that p.Ala341Asp is possibly damaging, and p.Tyr547Cys and p.His420Pro can be probably damaging (Table 2).
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ABCD1 p.His420Pro 23300730:101:80
status: NEW139 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).
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ABCD1 p.His420Pro 23300730:139:39
status: NEW140 These results confirm that p.Ala341Asp, p.Tyr547Cys and p.His420Pro are the causing disease mutations in each patient.
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ABCD1 p.His420Pro 23300730:140:58
status: NEW150 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).
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ABCD1 p.His420Pro 23300730:150:41
status: NEW170 Therefore, an alternative would be that p.His420Pro mutant might be misfolded on the peroxisomal membranes and unable to interact correctly with each ALDP or other peroxisomal ABC proteins such PMP70 or ALDRP [23-27] and are recruited to proteasomes for degradation.
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ABCD1 p.His420Pro 23300730:170:42
status: NEW