ABCMdb

PMID: 8040304

Fanen P, Guidoux S, Sarde CO, Mandel JL, Goossens M, Aubourg P
Identification of mutations in the putative ATP-binding domain of the adrenoleukodystrophy gene.
J Clin Invest. 1994 Aug;94(2):516-20., [PubMed]

Sentences

No. Mutations Sentence Comment

48 ABCC7 p.Ser1255Pro ABCC7 p.Ser549Arg ABCD1 p.Arg518Trp ABCD1 p.Arg617Cys ABCD1 p.Arg617His ABCD1 p.Ser606Leu Asterisks indicate the posi- *l I U13 | tion of the four missense mutations in ALD protein (ALDP): R518W substitution occurs at the same amino acid position as in the CFTR mutant S1255P, and S606L at the same position as in the S5491 or S549R CFTR mutants; R617C and R617H have no equivalents in CFTR mutants. Login to comment 81 ABCD1 p.Arg518Trp This mutation (Arg 518 -+ Trp or R518W in the single letter amino acid code) (Fig. 3) causes a nonconservative change between a charged and strongly polar (basic) amino acid and a hydrophobic nonpolar amino acid (Fig. 1). Login to comment 88 ABCD1 p.Ser606Leu The C2203 -+ T (Ser6O6 -+ Leu or S606L) mutation was identified in a patient who had Addison's disease without neurologic involvement at 20 years. Login to comment 90 ABCD1 p.Arg617Cys The C2235 -+ T (Arg617 -+ Cys or R617C) mutation was discovered in a family where the index case died of cerebral ALD at 9 years. Login to comment 93 ABCD1 p.Arg617His The third missense mutation (G2236 -- A) involved the same codon (Arg617 -+ His or R617H) and was discovered in a patient who developed AMN with cerebral involvement at 33 years. Login to comment 96 ABCD1 p.Arg617His Therefore, the R617H mutation presented by this patient is likely to be a de novo mutation. Login to comment 97 ABCD1 p.Arg518Trp These three missense mutations and the R518W were not observed in 100 normal X chromosomes, strongly suggesting that they are deleterious. Login to comment 108 ABCD1 p.Arg464* The R464X mutation was found in one patient who had Addison's disease at 10 A G CT nt 1935 G -M G -N.- A _ T nt 1943 Control Phe 51 7 Arg 518 lle 519 AG CT nt 1935 - / T]Phe ._/C_ 517 _ -.4 T -> w *. Login to comment 109 ABCD1 p.Arg518Trp G Trp - G7 518 lie \t-519 nt 1943 R518W AGCT nt1935 _ / T Phe ~C_ 517 G. ml -> G Gly _.__ A 518 = T- _m C Ser - 519 nt 943 1 937delC Figure 3. Login to comment 110 ABCD1 p.Arg518Trp Partial nucleotide sequence of exon 6 in control, in the AMN patient with the R518W mutation and in the abnormal allele of the heterozygous mother with the 1937delC mutation. Login to comment 127 ABCD1 p.Arg617Cys ABCD1 p.Arg617His ABCD1 p.Ser606Leu Three of them (S606L, R617C, and R617H) involve invariant residues in all ABC proteins studied so far (Fig. 1). Login to comment 138 ABCB1 p.Lys1076Met ABCB1 p.Lys433Met ABCD1 p.Arg518Trp The chloride channel activity of the CFTR mutant S 1255P, which involves the same amino acid position in the NBF as in the ALD mutant R518W, is less sensitive to ATP stimulation (24) and the MDR mutants K433M or K1076M within the same Walker motif are unable to hydrolyze ATP (25). Login to comment 143 ABCC7 p.Ser549Arg ABCD1 p.Ser606Leu The CFTR mutants S5491 and S549R, that involve the same amino acid position as in the ALD mutant S606L, fail to produce mature CFTR and therefore prevent trafficking to the correct cellular localization ( 12). Login to comment 145 ABCD1 p.Arg464* ABCD1 p.Arg518Trp ABCD1 p.Arg617Cys ABCD1 p.Arg617His ABCD1 p.Ser606Leu Mutations Detected in the ALD Gene Name Nucleotide change Effect on coding sequence Exon Clinical phenotype R464X C - T at 1776 Arg - Stop at 464 4 AMN* 1937delC Deletion of C at 1937 Frameshift 6 cerebral ALD R518W CT at 1938 Arg-Trpat 518 6 AMN 2020 + I G - A G - A at 2020 + 1 5' splice signal Intron 6 ACMN2 2177delTA Deletion of TA at 2177 Frameshift 8 cerebral ALD S606L C - T at 2203 Ser - Leu at 606 8 Addison 2204delG Deletion of G at 2204 Frameshift 8 Addison R617C C - T at 2235 Arg - Cys at 617 8 cerebral ALD R617H G - A at 2236 Arg - His at 617 8 ACMN * Adrenomyeloneuropathy; tadrenomyeloneuropathy with cerebral involvement. Login to comment