ABCMdb

ABCD1 p.Ser515Phe

ClinVar:	c.1544C>T , p.Ser515Phe D , Pathogenic
Predicted by SNAP2:	A: D (85%), C: D (91%), D: D (95%), E: D (95%), F: D (95%), G: D (91%), 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%), T: D (91%), 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, R: D, T: D, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[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.

Comments [show]

None has been submitted yet.

Sentences [show]
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. Login to comment

[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]

Abstract [show]

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
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. Login to comment
43 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). Login to comment
44 Co-segregation was confirmed between the disease phenotype and the mutations predicting Y174D, and S515F (Fig. 3), as well as for G266R (Fig. 1), and N148S (data not shown). Login to comment
45 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. Login to comment
50 (C) Loss of a Sad site due to the C1930T transition (S515F). Login to comment
56 In the case of the S515F mutation, as S515 is present in one of the ATP-binding folds which is entirely conserved between ALD and PMP70 (13), the amino acid substitution might well disturb the correct binding of ATP. Login to comment

[hide] A missense point mutation (Ser515Phe) in the adren... J Neurol Neurosurg Psychiatry. 1995 Feb;58(2):229-31. Vorgerd M, Fuchs S, Tegenthoff M, Malin JP
A missense point mutation (Ser515Phe) in the adrenoleukodystrophy gene in a family with adrenomyeloneuropathy: a clinical, biochemical, and genetic study.
J Neurol Neurosurg Psychiatry. 1995 Feb;58(2):229-31., [PMID:7876858]

Abstract [show]
A 36 year old male patient with adrenomyeloneuropathy (AMN) developed progressive spastic paraparesis and sensory ataxia from the age of 18. Biochemical studies showed increased plasma concentrations of saturated very long chain fatty acids (VLCFAs), subclinical evidence of adrenal insufficiency, and primary hypogonadism. Three female family members had increased plasma concentrations of VLCFAs, suggesting carrier status of adrenoleukodystrophy (ALD). Molecular genetic analysis detected a missense point mutation (C1930T) in exon 6 within the ALD gene, which predicts substitution of an amino acid (Ser515Phe) that is conserved between the deduced amino acid sequence of the peroxisomal membrane protein PMP70 and ALD protein. Detection of this point mutation allows diagnosis of ALD or AMN, identification of heterozygotes, and prenatal diagnosis of ALD.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
32 Direct sequencing of this particular segment showed a single nucleotide substitution (CI 930T) in the patient's sequence (fig 2), predicting the replacement of serine to phenylalanine at position 515 (Ser5 1 5Phe) in the deduced amino acid sequence of the ALD gene (numbering of nucleotides and amino acids to the ALD cDNA sequence as in Mosser et al 4). Login to comment
35 As r515Phe) shown in fig 1 the Ser515Phe mutation could indred with also be detected in a heterozygous manner in and 6, wild the three female relatives of the patient-who zizygous loss also showed increased VLCFA concentra- (SerSI5Phe) tions but not in the unaffected father. Login to comment
55 10 Molecular genetic analysis of the genomic DNA of the patient with AMN presented in this study detected a missense point mutation (C1930T) in exon 6 of the ALD gene that predicts the change of serine to phenylalanine at position 515 (Ser515Phe) in the deduced amino acid sequence. Login to comment
57 If the Ser515Phe substitution found in the family was the only mutation present in the ALD gene, as our results suggest, it could be the likely cause of the disease. Login to comment
60 Analysis of DNA of the patient's mother, maternal grandmother, and sister showed that they carry the ALD mutation Ser515Phe in a heterozygous manner. Login to comment
62 Identification of the Ser515Phe mutation principally allows prenatal diagnosis of ALD or AMN. Login to comment
94 with adrenomyeloneuropathy: a clinical, the adrenoleukodystrophy gene in a family A missense point mutation (Ser515Phe) in http://jnnp.bmj.com/content/58/2/229 Updated information and services can be found at: These include: References http://jnnp.bmj.com/content/58/2/229#related-urls Article cited in: service Email alerting the box at the top right corner of the online article. Login to comment
92 adrenomyeloneuropathy: a clinical, adrenoleukodystrophy gene in a family with A missense point mutation (Ser515Phe) in the M Vorgerd, S Fuchs, M Tegenthoff and J P Malin doi: 10.1136/jnnp.58.2.229 1995 58: 229-231 J Neurol Neurosurg Psychiatry http://jnnp.bmj.com/content/58/2/229 Updated information and services can be found at: These include: service Email alerting box at the top right corner of the online article. Login to comment

[hide] Adult cerebral adrenoleukodystrophy and Addison's ... Gene. 2014 Jul 10;544(2):248-51. doi: 10.1016/j.gene.2014.04.056. Epub 2014 Apr 25. Chen X, Chen Z, Huang D, Liu X, Gui Q, Yu S
Adult cerebral adrenoleukodystrophy and Addison's disease in a female carrier.
Gene. 2014 Jul 10;544(2):248-51. doi: 10.1016/j.gene.2014.04.056. Epub 2014 Apr 25., [PMID:24768737]

Abstract [show]
We described a 38-year-old woman of rapidly progressive dementia with white matter encephalopathy and death. She had Addison's disease but the adrenal glands were hyperplastic. Brain magnetic resonance imaging revealed diffuse white matter lesion predominantly in the frontal lobe with band-like contrast enhancement. l-Methyl-11C-methionine positron emission tomography revealed accumulation of tracer in bilateral frontal lobes. Stereotactic biopsy demonstrated demyelination changes. A number of urinary organic acids were elevated. Adrenoleukodystrophy was diagnosed by elevated plasma very long chain fatty acid and ABCD1 gene mutation (C1544C/T). Adrenoleukodystrophy should be considered as a differential diagnosis in women with rapidly progressive white matter encephalopathy.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
48 The diagnosis of ALD was confirmed by elevated plasma level of VLCFA [hexacosanoic acid = 0.81 (0-0.5), C24:0/C22:0 = 1.99 (0-1.24), C26:0/C22:0 = 0.1 (0-0.02)] and the detection of missense mutation C1544C/T (Ser515Phe) on the ABCD1 gene of exon 6. Login to comment
103 We found a missense mutation (C1544C/T) in exon 6 of ABCD1 gene in this patient which predicts the replacement of serine to phenylalanine at position 515 (Ser515Phe). Login to comment