ABCMdb

PMID: 10190819

Takano H, Koike R, Onodera O, Sasaki R, Tsuji S
Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy.
Arch Neurol. 1999 Mar;56(3):295-300., [PubMed]

Sentences

No. Mutations Sentence Comment

39 ABCD1 p.Trp595* ABCD1 p.Trp595* Mutations in the ALD Gene That Result in Devastating Effects (Truncation) on ALDP* Patient No. Phenotype Mutation† Exon Effect of Mutation‡ Position of Mutation§ Family Data Large Genomic Rearrangement G4001(s) ACALD 0.5-kb deletion 1 Disruption of gene structure Exon 1 No family history G4002(s) ACALD 7-kb deletion 7-9 Disruption of gene structure Exons 7-8 No family history G4003(s) ACALD 10.6-kb deletion 6-10 Disruption of gene structure Exons 6-10 No family history Frameshift Mutation G4004 CCALD C488AT࿣ 1 Frameshift at P34 TM1 Symptomatic carrier G4005 ACALD ins.977T࿣ 1 Frameshift at L197 Between TM3 and TM4 Not available G4006 AMN del.1801-1802 5 Frameshift at E471 Between TM6 and Walker A Not available G4007(s) ACALD del.1801-1802 5 Frameshift at E471 Between TM6 and Walker A No family history G4008 CCALD del.1801-1802 5 Frameshift at E471 Between TM6 and Walker A Not available Nonsense Mutation G4009 CCALD G2171A࿣ 8 W595X Between Walker A and B CCALD *ALD indicates adrenoleukodystrophy; ALDP, ALD protein; ACALD, adult-onset cerebral ALD; CCALD, childhood cerebral ALD; AMN, adrenomyeloneuropathy; (s), apparently sporadic patients; ins., insert; and del., delete. Login to comment 42 ABCD1 p.Arg660Trp ABCD1 p.Arg660Trp ABCD1 p.Asn148Ser ABCD1 p.Tyr296Cys ABCD1 p.Tyr296Cys ABCD1 p.Tyr296Cys ABCD1 p.Tyr296Cys ABCD1 p.Gly266Arg ABCD1 p.Gly266Arg ABCD1 p.Gly266Arg ABCD1 p.Gly266Arg ABCD1 p.Arg518Gln ABCD1 p.Arg518Gln ABCD1 p.Arg518Gln ABCD1 p.Arg518Gln ABCD1 p.Ser606Leu ABCD1 p.Ser606Leu ABCD1 p.Phe540Ser ABCD1 p.Phe540Ser ABCD1 p.Arg401Trp ABCD1 p.Arg401Trp ABCD1 p.Gln544Arg ABCD1 p.Gln544Arg ABCD1 p.Glu271Lys ABCD1 p.Glu271Lys ABCD1 p.Asn214Asp ABCD1 p.Asn214Asp ABCD1 p.Arg591Trp ABCD1 p.Arg591Trp ABCD1 p.Gly507Val ABCD1 p.Gly507Val ABCD1 p.Asp200Asn ABCD1 p.Asp200Asn ABCD3 p.Asn148Ser Mutations in the ALD Gene That Result in Amino Acid Substitutions or In-frame Deletions* Patient No. Phenotype Mutation† Exon Effect of Mutation‡ Position of Mutation§ Amino Acid Identityሻ Family DataPMP70 mALDRP Pxa1p Amino Acid Deletion G4010 ACALD del.1256-1258 1 del.E291 EAA-like motif E E E CCALD G4011(s) ACALD del.2146-2157¶ 7 del.HILQ587-590 Between Walker A and B# HILE HIVQ YLLK No family history Missense Mutation G4012 CCALD A829G 1 N148S TM3 N N N AMN G1986 CCALD G984A¶ 1 D200N TM4 D D D ACALD G4013 CCALD A1026G¶ 1 N214D TM4 N N N Not available G4014 AMN G1182A 1 G266R Between TM5 and EAA motif G G Non AMN G4015(s) CCALD G1182A 1 G266R Between TM5 and EAA motif G G Non No family history G4016(s) AMN G1197A 1 E271K Between TM5 and EAA motif T E R No family history G4017(s) ACALD A1273G¶ 1 Y296C EAA motif Y Y Y No family history G4018 CCALD A1273G¶ 1 Y296C EAA motif Y Y Y Not available G4019 AMN C1587T¶ 3 R401W Between TM6 and Walker A R R R Asymptomatic carrier G4020 CCALD G1906T¶ 6 G507V Walker A# G G G Not available G4021 CCALD G1939A 6 R518Q Walker A# R R R CCALD G4022 CCALD G1939A 6 R518Q Walker A# R R R Not available G4023 ACALD T2005C¶ 6 F540S Between Walker A and B# F F F Adult asymptomatic carrier G4024(s) CCALD A2017G 6 Q544R Between Walker A and B# Q Q Q No family history G4025 CCALD C2065T 7 S560L Between Walker A and B# P P P Adult asymptomatic carrier G2469(s) ACALD C2157T¶ 7 R591W Between Walker A and B# R R R No family history G2022(s) AMN C2203T 8 S606L Between Walker A and B# S S S No family history G4026 ACALD C2364T 8 R660W C-terminal to Walker B R R R ACALD *ALD indicates adrenoleukodystrophy; ACALD, adult-onset cerebral ALD; CCALD, childhood cerebral ALD; AMN, adrenomyeloneuropathy; (s), apparently sporadic patients; and del., delete. Login to comment 64 ABCD1 p.Gly266Arg Among the 5 mutations associated with AMN in this study, 2 (del.1801-1802 and G266R) were also associated with CCALD and ACALD. Login to comment 65 ABCD1 p.Ser606Leu ABCD1 p.Ser606Leu ABCD1 p.Arg401Trp ABCD1 p.Glu271Lys Although each of the remaining 3 mutations (E271K, R401W, and S606L) was identified in only 1 apparently sporadic case of a patient with AMN, a review of the literature indicated that the S606L mutation has been identified in 2 patients with Addison disease only but in no patients with CCALD.33,46 COMMENT MUTATIONS IN THE ALD GENE Because of the low frequency (4%-7%) of large genomic rearrangements in the ALD gene,26,33,34 a detailed nucleotide sequence analysis to detect small nucleotide alterations is required for most cases of ALD. Login to comment 85 ABCD1 p.Ser606Leu In the present study, 1 patient with AMN with no family history was identified to have the C2203T (S606L) mutation, although it had previously been reported33,46 to beassociatedexclusivelywiththeAddisondiseaseonlyphe- notype in other studies. Login to comment 86 ABCD1 p.Arg401Trp ABCD1 p.Glu271Lys Similar to this mutation, the mu- tationsG1197A(E271K)andC1587T(R401W)wereiden- tified in patients with AMN with no family history of ALD in the present study. Login to comment 87 ABCD1 p.Arg104His ABCD1 p.Ala294Thr ABCD1 p.Ser149Asn ABCD1 p.Arg389His ABCD1 p.Thr105Ile ABCD1 p.Arg104Cys ABCD1 p.Gln178Glu ABCD1 p.Arg389Gly ABCD1 p.Leu220Pro ABCD1 p.Ser515Phe ABCD3 p.Glu606Lys ABCD1 p.Thr254Met ABCD1 p.Met566Lys ABCD1 p.Arg418Trp Review of previous publications indicated that 14 missense mutations are associated exclu- sivelywithAMNorAddisondiseaseonly,includingC696T (R104C),33,34 G697A(R104H),42 C700T(T105I),45 G832A (S149N),35 C918G(Q178E),42 T1045C(L220P),35 C1137T (T254M),37 G1266A(A294T),45 C1551G(R389G),37 G1552A (R389H),33,35 C1638T (R418W),37 C1930T (S515F),38 T2084A(M566K),33 andG2211A(E606K).35,37 Analysisof these mutations may provide important insights into the mechanisms involved in variable phenotypic expressions in ALD. Login to comment 88 ABCD1 p.Asn148Ser It is well known that more than 1 clinical phenotype can appear within a single pedigree.6-8 In 1 kindred, a missense mutation was associated with 5 different phenotypes.43 In the present study, 1 patient with CCALD with the A829G (N148S) mutation had a brother with AMN. Login to comment