ABCD1 p.Arg17His
| Predicted by SNAP2: | A: N (61%), C: N (57%), D: D (71%), E: D (53%), F: D (75%), G: D (53%), H: N (61%), I: N (57%), K: N (97%), L: N (57%), M: N (61%), N: N (57%), P: D (59%), Q: N (82%), S: N (66%), T: N (66%), V: N (61%), W: D (80%), Y: D (71%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: D, N: N, P: N, Q: N, S: N, T: N, V: D, W: D, Y: D, |
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[hide] X-linked adrenoleukodystrophy in Spain. Identifica... Clin Genet. 2005 May;67(5):418-24. Coll MJ, Palau N, Camps C, Ruiz M, Pampols T, Giros M
X-linked adrenoleukodystrophy in Spain. Identification of 26 novel mutations in the ABCD1 gene in 80 patients. Improvement of genetic counseling in 162 relative females.
Clin Genet. 2005 May;67(5):418-24., [PMID:15811009]
Abstract [show]
In this study, we analyzed the ABCD1 gene in 80 X-linked adrenoleukodystrophy (X-ALD) patients from 62 unrelated families. We identified 53 different mutations, of which 26 are novel and two are non-pathogenic sequence variants (L516L and 3'UTR, 2246C/G) that have been previously described. The Spanish population had significant allelic heterogeneity, in which most of the mutations were exclusive to a single family 47/53 (88.7%). Only six mutations (Y174S, G277R, FsE471, R518Q, P543L, and R554H) were found in more than one family. Mutations G277R, P543L, and R554H were the most frequent, each of them being found in three patients (5%). Intra-familiar phenotype variability was observed in most of the families, but in one, with the novel mutation R120P, only the adult mild phenotype was present (five hemizygous family members). We detected 80 heterozygous women by mutation analysis, but only 78 of them showed increased very-long-chain fatty acid levels. In conclusion, this study extends the spectrum of mutations in X-ALD and facilitates the identification of heterozygous females. Our results are also consistent with previous studies reporting the difficulty of predicting genotype-phenotype correlation.
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No. Sentence Comment
41 The novel mutations included 12 amino acid substitutions [R17H, V102E, R120P, N148Y, G277R (829G> C), L279P, A396T, M501L, K533E, D561V, R617L, and S656F], five stop codon (S108X, S358X, W524X, Q567X, and S572X), one acceptor splice site mutation (IVS1-3C > G), and nine frameshift mutations as a consequence of four deletions [FsS453 (1359delT), FsG473 (1420delA), FsA616 (1847delC), and Fs N390 (1171delTCCTGACAGC)], one insertion [FsW326 (979insT)], and three complex mutations [FsQ38 (115delTG CCTGGCCCCGGCCAGinsGCA, FsF252 (757 delCTCACGGCC insGAGG), and FsL504 (1515 delCACAGinsGCA)].
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ABCD1 p.Arg17His 15811009:41:58
status: NEW67 With respect to the 12 missense mutations (R17H, V102E, R120P, N148Y, G277R, L279P, A396T, M501L, K533E, D561V, R617L, and S656F), only in four cases (L279P, K533E, R554H, and S656F mutations), three of which (K533E, R554H, and S656F) affect adenosine triphosphate-binding domain or boundaries, could negative ALDP protein expression be established.
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ABCD1 p.Arg17His 15811009:67:43
status: NEW68 However, several lines of evidence suggest that all these mutations may be pathogenic: (a) after screening the entire coding region of the ABCD1 gene, no other mutation was found in these patients, except for patient A302, who has two changes at the same allele: R17H and FsG473, the later being most certainly the disease-causing mutation.
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ABCD1 p.Arg17His 15811009:68:263
status: NEW69 Therefore, although we did not detect it in controls, it is very probable that R17H is a new polymorphism; (b) none of the novel mutations was detected when 100 normal chromosomes were analyzed; (c) all the amino acid residues, except R120, are conserved among the proteins belonging to the ABC subfamily D.
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ABCD1 p.Arg17His 15811009:69:79
status: NEW