ABCMdb

PMID: 15811009

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., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCD1 p.Pro543Leu ABCD1 p.Arg554His ABCD1 p.Arg518Gln ABCD1 p.Tyr174Ser ABCD1 p.Gly277Arg Only six mutations (Y174S, G277R, FsE471, R518Q, P543L, and R554H) were found in more than one family. Login to comment 7 ABCD1 p.Pro543Leu ABCD1 p.Arg554His ABCD1 p.Gly277Arg Mutations G277R, P543L, and R554H were the most frequent, each of them being found in three patients (5%). Login to comment 8 ABCD1 p.Arg120Pro 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). Login to comment 41 ABCD1 p.Gly277Arg ABCD1 p.Arg120Pro ABCD1 p.Gln567* ABCD1 p.Lys533Glu ABCD1 p.Leu279Pro ABCD1 p.Asn148Tyr ABCD1 p.Arg617Leu ABCD1 p.Arg17His ABCD1 p.Ser108* ABCD1 p.Ser358* ABCD1 p.Trp524* ABCD1 p.Ser572* ABCD1 p.Ser656Phe ABCD1 p.Ala396Thr ABCD1 p.Val102Glu ABCD1 p.Met501Leu ABCD1 p.Asp561Val 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)]. Login to comment 65 ABCD1 p.Gln567* ABCD1 p.Ser108* ABCD1 p.Ser358* ABCD1 p.Trp524* ABCD1 p.Ser572* In relation to the 26 new mutations, all frameshifts caused by deletions (FsN390, FsS453, FsG473, and FsA616), complex mutations (FsQ38, FsF252, and FsL504), or nonsense mutations (S108X, S358X, W524X, Q567X, and S572X) result in truncation and negative expression of the ALDP mutant protein. Login to comment 67 ABCD1 p.Arg554His ABCD1 p.Arg554His ABCD1 p.Gly277Arg ABCD1 p.Arg120Pro ABCD1 p.Lys533Glu ABCD1 p.Lys533Glu ABCD1 p.Lys533Glu ABCD1 p.Leu279Pro ABCD1 p.Leu279Pro ABCD1 p.Asn148Tyr ABCD1 p.Arg617Leu ABCD1 p.Arg17His ABCD1 p.Ser656Phe ABCD1 p.Ser656Phe ABCD1 p.Ser656Phe ABCD1 p.Ala396Thr ABCD1 p.Val102Glu ABCD1 p.Met501Leu ABCD1 p.Asp561Val 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. Login to comment 68 ABCD1 p.Arg17His 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. Login to comment 69 ABCD1 p.Arg17His 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. Login to comment 70 ABCD1 p.Arg120Pro In the case of mutation R120P, cosegregation in other family members was established (four hemizygous and five heterozygous members previously diagnosed by increased levels of C26 in serum and/or fibroblasts). Login to comment 72 ABCD1 p.Pro543Leu ABCD1 p.Arg554His ABCD1 p.Arg518Gln ABCD1 p.Tyr174Ser ABCD1 p.Gly277Arg Only six mutations (Y174S, G277R, FsE471, R518Q, P543L, and R554H) have been found repeated in patients belonging to different families. Login to comment 74 ABCD1 p.Pro543Leu ABCD1 p.Arg554His ABCD1 p.Gly277Arg In contrast, mutations G277R, P543L, and R554H are the most frequent in the Spanish population, each one accounting for three independent patients (5%) with different phenotypes, as occurs in other populations (for more information: http://www.x-ald.nl). Login to comment