ABCMdb

ABCD1 p.Asp200Asn

Predicted by SNAP2:	A: D (95%), C: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Mutational analysis and genotype-phenotype correla... Arch Neurol. 1999 Mar;56(3):295-300. 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., [PMID:10190819]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (ALD) is an inherited disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency. The classic form of ALD usually has onset in childhood (childhood cerebral ALD), with rapid neurologic deterioration leading to a vegetative state. Adult-onset cerebral ALD also presents with rapidly progressive neurologic dysfunction. Milder phenotypes such as adrenomyeloneuropathy and Addison disease only also have been recognized. Despite discovery of the causative gene, a molecular basis for the diverse clinical presentations remains to be elucidated. OBJECTIVES: To conduct mutational analyses in 29 Japanese patients with ALD from 29 unrelated families, to obtain knowledge of the spectrum of mutations in this gene, and to study genotype-phenotype correlations in Japanese patients. METHODS: The 29 patients comprised 13 patients with childhood cerebral ALD, 11 patients with adult-onset cerebral ALD, and 5 patients with adrenomyeloneuropathy. We conducted detailed mutational analyses of 29 unrelated Japanese patients with ALD by genomic Southern blot analysis and direct nucleotide sequence analysis of reverse transcriptase-polymerase chain reaction products derived from total RNA that was extracted from cultured skin fibroblasts, lymphoblastoid cells, or peripheral blood leukocytes. RESULTS: Three patients with adult-onset cerebral ALD were identified as having large genomic rearrangements. The remaining 26 patients were identified as having 21 independent mutations, including 12 novel mutations resulting in small nucleotide alterations in the ALD gene. Eighteen (69%) of 26 mutations were missense mutations. Most missense mutations involved amino acids conserved in homologous gene products, including PMP70, mALDRP, and Pxa1p. The AG dinucleotide deletion at position 1081-1082, which has been reported previously to be the most common mutation in white patients (12%-17%), was also identified as the most common mutation in Japanese patients (12%). All phenotypes were associated with mutations resulting in protein truncation or subtle amino acid changes. There were no differences in phenotypic expressions between missense mutations involving conserved amino acids and those involving nonconserved amino acids. CONCLUSIONS: There are no obvious correlations between the phenotypes of patients with ALD and their genotypes, suggesting that other genetic or environmental factors modify the phenotypic expressions of ALD.

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No. Sentence Comment
42 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

[hide] Mutations, clinical findings and survival estimate... PLoS One. 2012;7(3):e34195. doi: 10.1371/journal.pone.0034195. Epub 2012 Mar 29. Pereira Fdos S, Matte U, Habekost CT, de Castilhos RM, El Husny AS, Lourenco CM, Vianna-Morgante AM, Giuliani L, Galera MF, Honjo R, Kim CA, Politei J, Vargas CR, Jardim LB
Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy.
PLoS One. 2012;7(3):e34195. doi: 10.1371/journal.pone.0034195. Epub 2012 Mar 29., [PMID:22479560]

Abstract [show]
In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD) patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics. METHODS: X- ALD patients from Brazil, Argentina and Uruguay were invited to participate in molecular studies to determine their genetic status, characterize the mutations and improve the genetic counseling of their families. All samples were screened by SSCP analysis of PCR fragments, followed by automated DNA sequencing to establish the specific mutation in each family. Age at onset and at death, male phenotypes, genetic status of women, and the effect of family and of latitude of origin were also studied. RESULTS: We identified thirty-six different mutations (twelve novel). This population had an important allelic heterogeneity, as only p.Arg518Gln was repeatedly found (three families). Four cases carried de novo mutations. Intra-familiar phenotype variability was observed in all families. Out of 87 affected males identified, 65% had the cerebral phenotype (CALD). The mean (95% CI) ages at onset and at death of the CALD were 10.9 (9.1-12.7) and 24.7 (19.8-29.6) years. No association was found between phenotypic manifestations and latitude of origin. One index-case was a girl with CALD who carried an ABCD1 mutation, and had completely skewed X inactivation. CONCLUSIONS: This study extends the spectrum of mutations in X-ALD, confirms the high rates of de novo mutations and the absence of common mutations, and suggests a possible high frequency of cerebral forms in our population.

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No. Sentence Comment
55 NBF ND Northern Brazil 52/Male CALD p.Arg401Gly # E3 Missense c.1201C.G CGG.GGG - Inherited Southern Brazil 54/Female CALD p.Ser358fsX42 # E2 Frameshift+stop codon c.1074_1075insA Truncated TMD ND Northern Brazil 55/Female AMN p.Gly510Ser (http://www.x-ald.nl) E6 Missense c.1528G.A GGC.AGC NBF ND Northern Brazil 56/Male CALD p.Asp200Asn (Takano H et al., 1999) E1C Missense c.528G.A GAC.AAC TMD Inherited Northern Brazil 57/Male CALD p. Pro560Leu (Braun A et al., 1995) E7 Missense c.1679C.T CCG.CTG NBF Inherited Northern Brazil The number of family: the registration number in records of our lab. AMN: adrenomyeloneuropaty; AO: Addison only; #: new mutations identified in this study; NBF: nucleotide-binding fold; TMD: Transmembrane Domin; ND: not determined. Login to comment