ABCMdb

PMID: 11438993

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., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCD1 p.Lys217Glu ABCD1 p.Asn13Thr 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). Login to comment 6 ABCD1 p.Lys217Glu ABCD1 p.Lys217Glu Expression studies revealed that only K217E is a deleterious mutation, because a plasmid encoding ALDP with K217E was ineffective in the restoration of defective b-oxidation in X-ALD fibroblasts. Login to comment 7 ABCD1 p.Asn13Thr The N13T amino acid exchange, on the other hand, did not affect ALDP function. Login to comment 8 ABCD1 p.Asn13Thr Thus, N13T represents the first polymorphism causing an amino acid exchange in the ABCD1 gene. Login to comment 46 ABCD1 p.Ser98Leu ABCD1 p.Lys217Glu ABCD1 p.Lys217Glu ABCD1 p.Arg518Gln ABCD1 p.Ser633Ile ABCD1 p.Ala99Asp ABCD1 p.Gly608Asp ABCD1 p.Arg660Pro Phenotype (years) Therapy Exon (ATG=1) Allele residues site Polymorphisms 1 1 ccALD 15 None 1 c.97-100 Fs V32 +BsmFI c.2246 G>C del/TACC 2 2 ccALD 6 LO, GTO, BMT 1+IVS1 g.697-925/del 3 3 AMN 33 LO, GTO 3 c.1092/del/C Fs E363 -BsuRI 4 4 ccALD Died at None 5 c.1415-1416/del Fs E471 +TaaIe the age of 9 AGf 5 5 AMN 20 LO, GTO 1 c.293 C>Tg S98L TMS 1c -Eco52I c.2019 C>T c.2246 G>C 6 6 AMN 18 LO, GTO 1 c.296 C>A A99D TMS 1 +BsaHI c.1548 G>A c.2246 G>C 7 7a ADO 14 LO, GTO 1 c.649 A>G K217E TMS 3 +AvaIe c.38 A>C 7 7b ADO 9 LO, GTO 1 c.649 A>G K217E TMS 3 +AvaIe c.38 A>C 8 8 AMN 22 LO, GTO 6 c.1553 G>Ah R518Q Walker Ad +PflMI 9 9 ccALD 17b LO, GTO 8 c.1823 G>A G608D C sequenced +HphI c.-59 C>T c.1548 G>A c.2246 G>C 10 10 Asymptomatic 9 LO,GTO 9 c.1898 G>T S633I Conserved in mouse +MslI 11 11 ccALD 9 None 9 c.1979 G>C R660P Conserved in mouse -Cfr10I a Novel variants in boldface type. Login to comment 53 ABCD1 p.Ser98Leu g S98L: ccALD, asymptomatic [Feigenbaum et al., 1996]. Login to comment 54 ABCD1 p.Arg518Gln h R518Q: ccALD [Imamura et al., 1997; Takano et al., 1999]. Login to comment 69 ABCD1 p.Ala626Thr Cell Lines and Cell Culture SV40 transformed ALDP-deficient fibroblasts from a patient (mutation A626T) were kindly provided by Dr. K.D. Smith and Dr. L.T. Braiterman (Baltimore, MD; patient 11 in Watkins et al. [1995]). Login to comment 80 ABCD1 p.Lys217Glu ABCD1 p.Asn13Thr 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. Login to comment 98 ABCD1 p.Lys217Glu ABCD1 p.Asn13Thr 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). Login to comment 103 ABCD1 p.Lys217Glu When the two constructs, each carrying one substitution, were transfected into X-ALD fibroblasts, one of them, c.649A>G (K217E), was not able to restore defective β-oxidation. Login to comment 105 ABCD1 p.Asn13Thr In contrast, the second nucleotide exchange, c.38A>C (N13T), exhibits wild type ALDP function. Login to comment 107 ABCD1 p.Asn13Thr We conclude that N13T represents a polymorphism, but not a disease-causing mutation. Login to comment 121 ABCD1 p.Lys217Glu ABCD1 p.Asn13Thr 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). Login to comment 126 ABCD1 p.Asn13Thr 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. Login to comment 153 ABCD1 p.Asn13Thr The other novel polymorphism, N13T, is the first polymorphism in the ABCD1 gene ever found to exchange an amino acid. Login to comment