ABCD1 p.Asn13Thr
| Predicted by SNAP2: | A: D (59%), C: D (71%), D: D (75%), E: D (66%), F: D (85%), G: D (63%), H: D (71%), I: D (75%), K: D (63%), L: D (75%), M: D (75%), P: D (80%), Q: D (59%), R: D (66%), S: N (57%), T: N (66%), V: D (59%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] X-linked adrenoleukodystrophy: clinical, biochemic... Biochim Biophys Acta. 2006 Dec;1763(12):1721-32. Epub 2006 Jul 26. Berger J, Gartner J
X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects.
Biochim Biophys Acta. 2006 Dec;1763(12):1721-32. Epub 2006 Jul 26., [PMID:16949688]
Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is a clinically heterogeneous disorder ranging from the severe childhood cerebral form to asymptomatic persons. The overall incidence is 1:16,800 including hemizygotes as well as heterozygotes. The principal molecular defect is due to inborn mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein (ALDP), a transporter in the peroxisome membrane. ALDP is involved in the transport of substrates from the cytoplasm into the peroxisomal lumen. ALDP defects lead to characteristic accumulation of saturated very long-chain fatty acids, the diagnostic disease marker. The pathogenesis is unclear. Different molecular mechanisms seem to induce inflammatory demyelination, neurodegeneration and adrenocortical insufficiency involving the primary ABCD1 defect, environmental factors and modifier genes. Important information has been derived from the X-ALD mouse models; species differences however complicate the interpretation of results. So far, bone marrow transplantation is the only effective long-term treatment for childhood cerebral X-ALD, however, only when performed at an early-stage of disease. Urgently needed novel therapeutic strategies are under consideration ranging from dietary approaches to gene therapy.
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No. Sentence Comment
72 Interestingly, in one X-ALD patient two single base pair substitutions in exon 1 have been observed, both causing amino acid exchanges (N13T and K217E).
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ABCD1 p.Asn13Thr 16949688:72:136
status: NEW74 The N13T amino acid exchange, on the other hand, did not affect ALDP function, which is in agreement with the hypothesis that there is a reduced functional importance of the first 66 N-terminal amino acids of ALDP.
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ABCD1 p.Asn13Thr 16949688:74:4
status: NEW[hide] Eight novel ABCD1 gene mutations and three polymor... Hum Mutat. 2001;18(1):52-60. Dvorakova L, Storkanova G, Unterrainer G, Hujova J, Kmoch S, Zeman J, Hrebicek M, Berger J
Eight novel ABCD1 gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: The first polymorphism causing an amino acid exchange.
Hum Mutat. 2001;18(1):52-60., [PMID:11438993]
Abstract [show]
X-ALD is a neurological disorder associated with inherited defects in the ABCD1 (ALD) gene located on Xq28 and with impaired peroxisomal very long-chain fatty acid beta-oxidation. We examined the ABCD1 gene in probands from 11 unrelated X-ALD Czech and Slovak families by the direct sequencing of cDNA or genomic PCR products. In 10 families there were 10 different mutations, eight of which were novel. The spectrum of mutations consists of six point mutations, three microdeletions (1bp, 2bp, 4 bp), and one large deletion (229bp). In the 11th family we detected two novel single-base pair substitutions in exon 1 (c.38 A>C and c.649 A>G), both causing amino acid exchanges (N13T and K217E). Expression studies revealed that only K217E is a deleterious mutation, because a plasmid encoding ALDP with K217E was ineffective in the restoration of defective beta-oxidation in X-ALD fibroblasts. The N13T amino acid exchange, on the other hand, did not affect ALDP function. Thus, N13T represents the first polymorphism causing an amino acid exchange in the ABCD1 gene. As this polymorphism was observed neither in 100 control alleles nor in 300 X-ALD patients who have been sequenced so far world-wide, it seems to be very rare or unique. Two additional novel polymorphisms were found by the sequencing of the ABCD1 gene from our patients: c.-59 C/T in the 5'untranslated region and c.2019 C/T (F673F) in exon 10. The frequencies of these two polymorphisms, were 11/150 and 2/150 control alleles, respectively.
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No. Sentence Comment
5 In the 11th family we detected two novel single-base pair substitutions in exon 1 (c.38 A>C and c.649 A>G), both causing amino acid exchanges (N13T and K217E).
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ABCD1 p.Asn13Thr 11438993:5:143
status: NEW7 The N13T amino acid exchange, on the other hand, did not affect ALDP function.
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ABCD1 p.Asn13Thr 11438993:7:4
status: NEW8 Thus, N13T represents the first polymorphism causing an amino acid exchange in the ABCD1 gene.
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ABCD1 p.Asn13Thr 11438993:8:6
status: NEW80 The two plasmids, one carrying human ABCD1 cDNA with point mutation c.38A>C (resulting in amino acid exchange N13T) and another carrying point mutation c.649A>G (amino acid exchange K217E), were used for transfection experiments, together with the non-mutated human ABCD1 plasmid as a control.
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ABCD1 p.Asn13Thr 11438993:80:110
status: NEW98 In patients 7a and 7b (Table 1) we identified two different one-base substitutions in exon 1 (c.38A>C and c.649A>G), both of them causing an amino acid exchange (N13T and K217E).
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ABCD1 p.Asn13Thr 11438993:98:162
status: NEW105 In contrast, the second nucleotide exchange, c.38A>C (N13T), exhibits wild type ALDP function.
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ABCD1 p.Asn13Thr 11438993:105:54
status: NEW107 We conclude that N13T represents a polymorphism, but not a disease-causing mutation.
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ABCD1 p.Asn13Thr 11438993:107:17
status: NEW121 The β-oxidation of lignoceric acid versus palmitic acid (C24:C16) in X-ALD fibroblasts after transfection with normal (wt) and two mutatedABCD1 cDNA constructs (nucleotide exchanges c.38A>C and c.649A>G, leading to amino acid exchanges N13T and K217E, respectively).
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ABCD1 p.Asn13Thr 11438993:121:242
status: NEW126 Polymorphisms in the ABCD1 Gene Nucleotide Restriction Allele Exon changea Frequency site 5'UTR 1 -59C/T 0.073 (11/150)b +BsmAI N13T 1 38A/C Unique +BsmFI L515L 6 1548G/A 0.85 vs 0.15c F673F 10 2019C/T 0.013 (2/150)b +TaqI 3'UTR 10 2246C/G 0.76 vs 0.24c a Novel variants in boldface type.
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ABCD1 p.Asn13Thr 11438993:126:128
status: NEW153 The other novel polymorphism, N13T, is the first polymorphism in the ABCD1 gene ever found to exchange an amino acid.
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ABCD1 p.Asn13Thr 11438993:153:30
status: NEW[hide] X-linked adrenoleukodystrophy: clinical, metabolic... Biochim Biophys Acta. 2012 Sep;1822(9):1465-74. doi: 10.1016/j.bbadis.2012.03.012. Epub 2012 Mar 28. Kemp S, Berger J, Aubourg P
X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects.
Biochim Biophys Acta. 2012 Sep;1822(9):1465-74. doi: 10.1016/j.bbadis.2012.03.012. Epub 2012 Mar 28., [PMID:22483867]
Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease. The two main clinical phenotypes of X-ALD are adrenomyeloneuropathy (AMN) and inflammatory cerebral ALD that manifests either in children or more rarely in adults. About 65% of heterozygote females develop symptoms by the age of 60years. Mutations in the ABCD1 gene affect the function of the encoded protein ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane protein. ALDP deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues. While all patients have mutations in the ABCD1 gene, there is no general genotype-phenotype correlation. Environmental factors and a multitude of modifying genes appear to determine the clinical manifestation in this monogenetic but multifactorial disease. This review focuses on the clinical, biochemical, genetic and pathophysiological aspects of X-ALD.
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No. Sentence Comment
234 The mutation p.Asn13Thr, for example, has been shown to represent a polymorphism, as this mutation did not affect the ability to compensate for the lack of functional ALDP after transfection [65].
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ABCD1 p.Asn13Thr 22483867:234:15
status: NEW