ABCD1 p.Arg418Trp
| ClinVar: |
c.1252C>T
,
p.Arg418Trp
D
, Pathogenic
|
| Predicted by SNAP2: | A: D (95%), C: D (95%), D: 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%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: 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
87 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.
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ABCD1 p.Arg418Trp 10190819:87:317
status: NEW[hide] Variability of endocrinological dysfunction in 55 ... Eur J Endocrinol. 1997 Jul;137(1):40-7. Korenke GC, Roth C, Krasemann E, Hufner M, Hunneman DH, Hanefeld F
Variability of endocrinological dysfunction in 55 patients with X-linked adrenoleucodystrophy: clinical, laboratory and genetic findings.
Eur J Endocrinol. 1997 Jul;137(1):40-7., [PMID:9242200]
Abstract [show]
X-linked adrenoleucodystrophy (ALD) has been shown to be one of the most frequent causes of Addison's disease in men. It is characterized by an impaired peroxisomal beta-oxidation of very long chain fatty acids and is associated with mutations of the ALD gene resulting in a defective peroxisomal membrane transport protein. There is a striking variability of endocrinological and neurological symptoms in patients with ALD, with no clearly evident correlation between mutations of the ALD gene and the different neurological phenotypes. No data on endocrinological symptoms and the ALD genotype have been published so far. We report endocrinological, clinical, laboratory and molecular genetic data from 55 patients with ALD from 34 families. Endocrinological symptoms of adrenal insufficiency were observed in 33 patients, 20 of whom showed additional neurological symptoms of cerebral ALD or adrenomyeloneuropathy. Isolated neurological symptoms were seen in 12 patients; in nine patients there were neither endocrinological nor neurological symptoms. Mutations of the ALD gene (n = 28) were detected in 50 patients (including nine sets of brothers) from 32 families. No correlation was found between the ALD gene mutation and endocrinological dysfunction. However, we found that all sets of brothers were concordant for the endocrinological phenotype (cortisol synthesis was reduced in two sets and normal in seven sets), whereas four sets showed a discordant neurological phenotype. As yet unknown hereditary factors other than mutations within the ALD gene may interfere with the endocrinological phenotype more strongly than with the neurological phenotype of ALD.
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118 Start of Cortisol Start of Age at endocrine Basal increase neurological examination symptoms ACTH cortisol after i.v. ACTH symptoms ALD gene Patient (year-month) (year-month) (pmol/l) (nmol/l) (nmol/l) (year-month) mutation 1a 9-05 6-08 223 179 0 7-02 cALD 2252-10 G-A 1b 13-03 9-05 41 331 41 9-05 cALD 2252-10 G-A 2a 26-01 - 6 386 221 - R418W 2b 27-10 - 6 461 229 11-00 cALD R418W 3a 11-06 6-00 536 138 8 - S606L 3b 11-06 6-00 423 143 11 10-10 cALD S606L 4a 4-04 2-09 >330 127 141 - R617C 4b 5-06 3-11 >330 97 50 - R617C 4c 7-10 5-05 >330 50 6 6-03 cALD R617C 5a 10-06 - 8 433 290 8-02 cALD del 1257-9 5b 17-07 - 9 637 629 - del 1257-9 6a 27-00 24-00 >320 30 11 18-03 AMN L107P 6b 32-10 - 47 279 185 19-01 AMN L107P 7a 34-08 - 48 469 350 24-00 AMN R418W 7b 36-05 - 43 486 201 28-00 AMN R418W 8a 14-05 - 33 287 94 - 1801 del AG 8b 16-10 - 14 348 149 - 1801 del AG 9a 13-07 5-10 1094 36 6 - 740 del G 9b 157-04 1241 63 11 - 740 del G cALD, cerebral adrenoleucodystrophy; AMN, adrenomyeloneuropathy; -, no symptoms.
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ABCD1 p.Arg418Trp 9242200:118:338
status: NEWX
ABCD1 p.Arg418Trp 9242200:118:376
status: NEWX
ABCD1 p.Arg418Trp 9242200:118:749
status: NEWX
ABCD1 p.Arg418Trp 9242200:118:787
status: NEW[hide] Missense mutations are frequent in the gene for X-... Hum Mol Genet. 1994 Oct;3(10):1903-5. Fuchs S, Sarde CO, Wedemann H, Schwinger E, Mandel JL, Gal A
Missense mutations are frequent in the gene for X-chromosomal adrenoleukodystrophy (ALD).
Hum Mol Genet. 1994 Oct;3(10):1903-5., [PMID:7849723]
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42 Mutations identified in the ALD gene of 9 unrelated ALD patients/families Amino acid |Codon |Exon |ALDP-PMP70 | Restriction site Asnl48Ser Tyrl74Asp Gly266Arg Arg401Gln Arg418Trp Gln472-frameshift Glu477ter Ser515Phe AAC->AGC TAC->GAC GGG-»AGG CGG->CAG CGG->TGG delAG GAG-+TAG TCC-»TTC I I I III IV V V VI conserved conserved conserved conserved conserved conserved none +TaqI none none - Smal none none -Sad that are conserved between the ALD protein and PMP70.
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ABCD1 p.Arg418Trp 7849723:42:169
status: NEW43 These missense mutations are (positions of nucleotides and amino acids according to the ALD cDNA sequence in ref. 4) A829G (N148S), T906G (Y174D), Gl 182A (G266R), G1588A (R401Q), C1638T (R418W), and C1930T (S515F).
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ABCD1 p.Arg418Trp 7849723:43:188
status: NEW45 For R401Q and R418W the families •e« M 1 2 3 4 5 B R418W C S515F r 1 2 3 4 5 6 M bp Figure 3. Identification of ALD mutations by restriction enzyme digestion.
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ABCD1 p.Arg418Trp 7849723:45:14
status: NEWX
ABCD1 p.Arg418Trp 7849723:45:63
status: NEW49 (B) The C1638T transition (R418W) destroys a Smal site. Lane 1: DNA of unaffected control.
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ABCD1 p.Arg418Trp 7849723:49:27
status: NEW[hide] Glutathione imbalance in patients with X-linked ad... Mol Genet Metab. 2013 Aug;109(4):366-70. doi: 10.1016/j.ymgme.2013.05.009. Epub 2013 May 22. Petrillo S, Piemonte F, Pastore A, Tozzi G, Aiello C, Pujol A, Cappa M, Bertini E
Glutathione imbalance in patients with X-linked adrenoleukodystrophy.
Mol Genet Metab. 2013 Aug;109(4):366-70. doi: 10.1016/j.ymgme.2013.05.009. Epub 2013 May 22., [PMID:23768953]
Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder of X-linked inheritance caused by a mutation in the ABCD1 gene which determines an accumulation of long-chain fatty acids in plasma and tissues. Recent evidence shows that oxidative stress may be a hallmark in the pathogenesis of X-ALD and glutathione plays an important role in the defense against free radicals. In this study we have analyzed glutathione homeostasis in lymphocytes of 14 patients with X-ALD and evaluated the balance between oxidized and reduced forms of glutathione, in order to define the role of this crucial redox marker in this condition. METHODS: Lymphocytes, plasma and erythrocytes were obtained from the whole blood of 14 subjects with X-ALD and in 30 healthy subjects. Total, reduced and protein-bound glutathione levels were measured in lymphocytes by HPLC analysis. Erythrocyte free glutathione and antioxidant enzyme activities, plasma thiols and carbonyl content were determined by spectrophotometric assays. RESULTS: A significant decrease of total and reduced glutathione was found in lymphocytes of patients, associated to high levels of all oxidized glutathione forms. A decline of free glutathione was particularly significant in erythrocytes. The increased oxidative stress in X-ALD was additionally confirmed by the decrease of plasma thiols and the high level of carbonyls. CONCLUSION: Our results strongly support a role for oxidative stress in the pathophysiology of X-ALD and strengthen the importance of the balance among glutathione forms as a hallmark and a potential biomarker of the disease.
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No. Sentence Comment
74 Subject Age (years) Phenotype Mutation HAAM 4 CCALD c.1415_1416delAG (p.Q472RfsX83) AM 24 CCALD c.919C>T (p.Q307X) SM 16 CCALD c.1888G>A (p.E630K) ON 11 CCALD c.1628C>T (p.P543L) MG 62 AMN c.2006A>G (p.H669R) AG 33 AMN c.427C>T (p.P143S) BM 64 AMN c.1382delT (p.L461RfsX97) PF 54 AMN c.1252C>T (p.R418W) RN 61 AMN c.1415_1416delAG (p.Q472RfsX83) ME 20 AMN c.442_444 del 3(AAC)/ins6 (TGTTGA) (p.N148CfsX1) SF 40 AMN c.442_444 del 3(AAC)/ins6 (TGTTGA) (p.N148CfsX1) LM 54 AMN c.1540A>C (p.S514R) LF 43 AMN c.1415_1416delAG (p.Q472RfsX83) LM 40 AMN c.1415_1416delAG (p.Q472RfsX83) 2.5.
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ABCD1 p.Arg418Trp 23768953:74:297
status: NEW