ABCMdb

ABCD1 p.His669Arg

Predicted by SNAP2:	A: N (57%), C: N (57%), D: D (59%), E: N (53%), F: N (61%), G: N (53%), I: N (53%), K: N (57%), L: N (78%), M: N (72%), N: N (61%), P: D (71%), Q: N (72%), R: N (66%), S: N (61%), T: N (57%), V: N (57%), W: N (66%), Y: N (87%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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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 In one patient 2 changes were found: a known missense (p.His669Arg) and an unpublished amino acid substitution (p.Ala19Ser).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
6 In one patient 2 changes were found: a known missense (p.His669Arg) and an unpublished amino acid substitution (p.Ala19Ser). 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
87 We identified nine different mutations: one missense mutation was previously described (p.His669Arg) and eight were new ones (Table 1). 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
132 The majority of X-ALD patients in our study group had non-recurrent (89%) mutations, except two patient (one of them Argentinean and the other of Italian origin) that had the same mutation p.His669Arg. 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
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
157 On the other hand according to the literature when the change p.His669Arg is present, ALDP was not observed in western blot. 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

[hide] Glutathione imbalance in patients with X-linked ad... Mol Genet Metab. 2013 Aug;109(4):366-70. doi: 10.1016/j.ymgme.2013.05.009. Epub 2013 May 22. Petrillo S, Piemonte F, Pastore A, Tozzi G, Aiello C, Pujol A, Cappa M, Bertini E
Glutathione imbalance in patients with X-linked adrenoleukodystrophy.
Mol Genet Metab. 2013 Aug;109(4):366-70. doi: 10.1016/j.ymgme.2013.05.009. Epub 2013 May 22., [PMID:23768953]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder of X-linked inheritance caused by a mutation in the ABCD1 gene which determines an accumulation of long-chain fatty acids in plasma and tissues. Recent evidence shows that oxidative stress may be a hallmark in the pathogenesis of X-ALD and glutathione plays an important role in the defense against free radicals. In this study we have analyzed glutathione homeostasis in lymphocytes of 14 patients with X-ALD and evaluated the balance between oxidized and reduced forms of glutathione, in order to define the role of this crucial redox marker in this condition. METHODS: Lymphocytes, plasma and erythrocytes were obtained from the whole blood of 14 subjects with X-ALD and in 30 healthy subjects. Total, reduced and protein-bound glutathione levels were measured in lymphocytes by HPLC analysis. Erythrocyte free glutathione and antioxidant enzyme activities, plasma thiols and carbonyl content were determined by spectrophotometric assays. RESULTS: A significant decrease of total and reduced glutathione was found in lymphocytes of patients, associated to high levels of all oxidized glutathione forms. A decline of free glutathione was particularly significant in erythrocytes. The increased oxidative stress in X-ALD was additionally confirmed by the decrease of plasma thiols and the high level of carbonyls. CONCLUSION: Our results strongly support a role for oxidative stress in the pathophysiology of X-ALD and strengthen the importance of the balance among glutathione forms as a hallmark and a potential biomarker of the disease.

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No. Sentence Comment
74 Subject Age (years) Phenotype Mutation HAAM 4 CCALD c.1415_1416delAG (p.Q472RfsX83) AM 24 CCALD c.919C>T (p.Q307X) SM 16 CCALD c.1888G>A (p.E630K) ON 11 CCALD c.1628C>T (p.P543L) MG 62 AMN c.2006A>G (p.H669R) AG 33 AMN c.427C>T (p.P143S) BM 64 AMN c.1382delT (p.L461RfsX97) PF 54 AMN c.1252C>T (p.R418W) RN 61 AMN c.1415_1416delAG (p.Q472RfsX83) ME 20 AMN c.442_444 del 3(AAC)/ins6 (TGTTGA) (p.N148CfsX1) SF 40 AMN c.442_444 del 3(AAC)/ins6 (TGTTGA) (p.N148CfsX1) LM 54 AMN c.1540A>C (p.S514R) LF 43 AMN c.1415_1416delAG (p.Q472RfsX83) LM 40 AMN c.1415_1416delAG (p.Q472RfsX83) 2.5. Login to comment

[hide] Mutational analyses on X-linked adrenoleukodystrop... Pediatr Neurol. 2013 Sep;49(3):185-90. doi: 10.1016/j.pediatrneurol.2013.04.021. Epub 2013 Jul 5. Hung KL, Wang JS, Keng WT, Chen HJ, Liang JS, Ngu LH, Lu JF
Mutational analyses on X-linked adrenoleukodystrophy reveal a novel cryptic splicing and three missense mutations in the ABCD1 gene.
Pediatr Neurol. 2013 Sep;49(3):185-90. doi: 10.1016/j.pediatrneurol.2013.04.021. Epub 2013 Jul 5., [PMID:23835273]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy is caused by a defective peroxisomal membrane transporter, ABCD1, responsible for transporting very-long-chain fatty acid substrate into peroxisomes for degradation. The main biochemical defect, which is also one of the major diagnostic hallmarks, of X-linked adrenoleukodystrophy is the accumulation of saturated very-long-chain fatty acids in all tissues and body fluids. METHODS: Direct and reverse-transcribed polymerase chain reactions followed by DNA sequencing-based mutational analyses were performed on one Taiwanese and three Malaysian X-linked adrenoleukodystrophy families. RESULTS: A novel splicing donor site mutation (c.1272+1g>a) was identified in a Taiwanese X-linked adrenoleukodystrophy patient, resulting in a deletion of 121 bp and a premature stop codon (p.Val425fs*92) in messenger-RNA transcript. This deletion is caused by the activation of a cryptic splicing donor site in exon 4 of the ABCD1 gene, which is consistent with the prediction by several online algorithms. In addition, three previously described missense mutations (c.965T>C, c.1978C>T, and c.2006A>G), leading to aberrant ABCD1 of p.Leu322Pro, p.Arg660Trp, and p.His669Arg, were also identified in Malaysian probands. CONCLUSIONS: This is the first report to unveil unequivocally that cryptic splicing-induced aberrant messenger-RNA carrying an internal frameshift deletion results from an intronic mutation in the ABCD1 gene. Furthermore, a polymorphism in intron 9 (c.1992-32c/t; refSNP: rs4898368) of the ABCD1 gene was commonly observed in both Taiwanese and Malaysian populations.

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5 In addition, three previously described missense mutations (c.965T>C, c.1978C>T, and c.2006A>G), leading to aberrant ABCD1 of p.Leu322Pro, p.Arg660Trp, and p.His669Arg, were also identified in Malaysian probands. Login to comment
78 This missense allele involved the replacement of a histidine by an arginine at position 669 of ABCD1 (p.His669Arg).24 In addition, a single nucleotide polymorphism, c.1992-32c/t (refSNP: rs4898368), localized to intron 9 of the ABCD1 gene, was also observed among Taiwanese and Malaysian populations (Table 2). Login to comment
98 Three missense mutations (c.965T>C, c.1978C>T, and c.2006A>G), leading to aberrant ABCD1 of p.Leu322Pro, p.Arg660Trp, and p.His669Arg, were also identified in Malaysian probands with X-ALD of the childhood cerebral form, adolescent cerebral phenotype, and adrenomyeloneuropathy with cerebral involvement, respectively. Login to comment
99 All three missense mutations have been reported to reoccur in three or more X-ALD kindred around the world.19-22,24 All three affected amino acids were highly conserved in ABCD1 among different species or among other peroxisomal ABC transporter homologues, suggesting their possible important role in maintaining proper ABCD1 structure or function.25-27 The replacement of leucine at position 322, localized to the fifth transmembrane domain of ABCD1, with proline is most likely to disrupt membrane spanning a-helical conformation because of the relatively high differences in free-energy change (DDG0 ) for proline to adapt a-helical conformation, as compared with that for alanine.28 On the other hand, both p.Arg660Trp and p.His669Arg, localized to the cytoplasmic domain of ABCD1, have been reported to affect protein stability, resulting in dramatic reduction (<3% in normal) in the amount of ABCD1 based on either immunofluorescence or immunoblotting.22,23,29 It is interesting to note that a cluster of stability affecting mutations involving the region between Pro654 and His669 near the carboxyl terminus of ABCD1 has no known structural or functional significance,22,23,30,31 suggesting their possible roles in cellular sensing or turnover of mutant proteins. Login to comment
113 In addition, three missense mutations (c.965T>C, c.1978C>T, and c.2006A>G), leading to aberrant ABCD1 of p.Leu322Pro, p.Arg660Trp, and p.His669Arg, were also identified in Malaysian X-ALD kindred. A polymorphism in intron 9 (c.1992-32c/t; refSNP: rs4898368) of the ABCD1 gene was also commonly observed in both Taiwanese and Malaysian populations. Login to comment