ABCMdb

PMID: 23835273

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., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCD1 p.Arg660Trp ABCD1 p.Leu322Pro ABCD1 p.His669Arg 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 56 ABCD1 p.Leu322Pro ABCD1 p.Leu322Pro Mutational analysis on genomic DNA revealed a T-to-C transition mutation (c.965T>C) at exon 2 of the ABCD1 gene, leading to the substitution of a leucine at position 322 to a proline (p.Leu322Pro) in ABCD1 (Fig 2).19,20 This transition mutation created a BspEI restriction site (50-T/CCGGA-30) from the original 50-TCTGGA-30 sequence, which can be useful for rapid screening of the mutant allele. Login to comment 75 ABCD1 p.Arg660Trp The mutation caused the conversion of a codon for arginine at position 660 to one encoding for a tryptophan (p.Arg660Trp) in ABCD1.21-23 Both the ALD-4 proband and his mother carried the A-toG transition mutation (c.2006A>G) in exon 10 of the ABCD1 gene based on genomic DNA typing results (Fig 3). Login to comment 78 ABCD1 p.His669Arg ABCD1 p.His669Arg 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 ABCD1 p.Arg660Trp ABCD1 p.Leu322Pro ABCD1 p.His669Arg 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 ABCD1 p.Arg660Trp ABCD1 p.His669Arg 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 ABCD1 p.Arg660Trp ABCD1 p.Leu322Pro ABCD1 p.His669Arg 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