ABCMdb

ABCD1 p.Arg152Cys

Predicted by SNAP2:	A: D (85%), C: D (91%), D: D (95%), E: D (91%), F: D (91%), G: D (91%), H: D (85%), I: D (91%), K: D (75%), L: D (91%), M: D (91%), N: D (85%), P: D (95%), Q: D (85%), S: D (75%), T: D (80%), V: D (91%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, 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 and protein analysis of patients and he... Am J Hum Genet. 1996 Jun;58(6):1135-44. Feigenbaum V, Lombard-Platet G, Guidoux S, Sarde CO, Mandel JL, Aubourg P
Mutational and protein analysis of patients and heterozygous women with X-linked adrenoleukodystrophy.
Am J Hum Genet. 1996 Jun;58(6):1135-44., [PMID:8651290]

Abstract [show]
X-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder associated with impaired beta-oxidation of very-long-chain fatty acids (VLCFA), is due to mutations in a gene encoding a peroxisomal ATP-binding cassette (ABC) transporter (ALD protein [ALDP]). We analyzed the open reading frame of the ALD gene in 44 French ALD kindred by using SSCP or denaturing gradient-gel electrophoresis and studied the effect of mutations on ALDP by immunocytofluorescence and western blotting of fibroblasts and/or white blood cells. Mutations were detected in 37 of 44 kindreds and were distributed over the whole protein-coding region, with the exception of the C terminus encoded in exon 10. Except for two mutations (delAG1801 and P560L) observed four times each, nearly every ALD family has a different mutation. Twenty-four of 37 mutations were missense mutations leading to amino acid changes located in or close to putative transmembrane segments (TMS 2, 3, 4, and 5), in the EAA-like motif and in the nucleotide fold of the ATP-binding domain of ALDP. Of 38 ALD patients tested, 27 (71%) lacked ALDP immunoreactivity in their fibroblasts and/or white blood cells. More than half of missense mutations studied (11 of 21) resulted in a complete lack of ALDP immunoreactivity, and six missense mutations resulted in decreased ALDP expression. The fibroblasts and/or white blood cells of 15 of 15 heterozygous carrier from ALD kindred with no ALDP showed a mixture of positive- and negative-ALDP immunoreactivity due to X-inactivation. Since 5%-15% of heterozygous women have normal VLCFA levels, the immunodetection of ALDP in white blood cells can be applicable in a majority of ALD kindred, to identify heterozygous women, particularly when the ALD gene mutation has not yet been identified.

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76 58:1135-1144, 1996 Table 2 Mutations in the ALD Gene in Studied Patients AMINO ACID MUTATIONSb HOMOLOGUE INd KINDRED CLINICAL LOCALIZATION AMINO ACID ALDP BY NUMBER PHENOTYPEa DNA CpG Exon IN PROTEINC ALTERATION h/m ALDRP hPMP70 IF/WB' CALD, AMN CALD CALD CALD, AS AD CALD, AMN CALC AD AD AD ALMD CALD CALD, AMN CALD CALD, AMN, AD AMN ALMD CALD ALMD CALD AMN ALD AD, AMN, AS CALD, AS CALD CALD AD CALD AMN, ALMD CALD CALD AMN, ALMD CALD CALD, AMN, ALMD CALD CALD, ALMD, AS ALMD CALD AMN CALD, AMN AD AD AMN CALD G416A Ins T524 C679T C679T C700T C709G G732A A829G C840T Del TA927-28 A928G A985T A1048G DeIGC1080-81 C1174T G1266A ins C1521 1636delC DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 ins TGG 1848 G 1920 A C1938T C1938T G1950A C2065T C2065T C2065T C2065T C2065G G 2166+1 A T2202C DelGC 2335 C2364T C2364T No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found 1 1 + 1 + 1 1 1 + 1 1 + 1 1 1 1 1 1 1 + 1 3 4 S 5 S S S 6 + 6 + 6 6 + 7 + 7 + 7 + 7 + 7 + 7 8 9 9 9 W10 X Frameshift at L46 TMS2 S98L TMS2 S98L T1OSI S108W G116R TMS3 N148S TMS3 R152C Frameshift at Y180 Y181C TMS4 D200V TMS4 D221G Frameshift at R231 P263L EAA-like A294T Frameshift at V378 Frameshift at T416 Frameshift at E471 Frameshift at E471 Frameshift at E471 Frameshift at E471 ins val 491 Walker A G512S Walker A R518W Walker A R518W G 522 W P560L P560L P560L P560L P56OR Splice at G593 Walker B S606P Frameshift at D649 R660W R660W Absent Not done S A Present S A Present T T Absent S D Decreased G T Absent N N Present R K Present Absent Y Y Not done D D Not done D D Absent Absent P R Decreased A A Not done Absent Absent Absent Absent Absent Absent Absent G G Absent R R Absent R R Decreased G E Absent P P Decreased P P Decreased P P Decreased P P Absent P P Absent Not done S S Absent Absent R R Absent R R Absent Not done Absent Absent Absent Present Absent Absent a CALD = cerebral ALD (5-15 years); AMN = adrenomyeloneuropathy; ALMD = adrenomyeloneuropathy with cerebral involvement; AD = Addison disease; AS = Asymptomatic. Login to comment
88 C, ALD fibroblasts (R152C mutation) immunostained with mAb2B4, showing normal ALDP immunoreactivity. Login to comment
100 Double staining with anti-ALDP and anticatalase was performed in two ALD fibroblast lines with normal ALDP immunocytofluorescence (S98L and R152C mutants). Login to comment
174 Three missense mutations (S98L, N148S, and R152C) resulted in the synthesis of a stable but presumably nonfunctioning protein. Login to comment
75 58:1135-1144, 1996 Table 2 Mutations in the ALD Gene in Studied Patients AMINO ACID MUTATIONSb HOMOLOGUE INd KINDRED CLINICAL LOCALIZATION AMINO ACID ALDP BY NUMBER PHENOTYPEa DNA CpG Exon IN PROTEINC ALTERATION h/m ALDRP hPMP70 IF/WB' CALD, AMN CALD CALD CALD, AS AD CALD, AMN CALC AD AD AD ALMD CALD CALD, AMN CALD CALD, AMN, AD AMN ALMD CALD ALMD CALD AMN ALD AD, AMN, AS CALD, AS CALD CALD AD CALD AMN, ALMD CALD CALD AMN, ALMD CALD CALD, AMN, ALMD CALD CALD, ALMD, AS ALMD CALD AMN CALD, AMN AD AD AMN CALD G416A Ins T524 C679T C679T C700T C709G G732A A829G C840T Del TA927-28 A928G A985T A1048G DeIGC1080-81 C1174T G1266A ins C1521 1636delC DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 ins TGG 1848 G 1920 A C1938T C1938T G1950A C2065T C2065T C2065T C2065T C2065G G 2166+1 A T2202C DelGC 2335 C2364T C2364T No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found 1 1 + 1 + 1 1 1 + 1 1 + 1 1 1 1 1 1 1 + 1 3 4 S 5 S S S 6 + 6 + 6 6 + 7 + 7 + 7 + 7 + 7 + 7 8 9 9 9 W10 X Frameshift at L46 TMS2 S98L TMS2 S98L T1OSI S108W G116R TMS3 N148S TMS3 R152C Frameshift at Y180 Y181C TMS4 D200V TMS4 D221G Frameshift at R231 P263L EAA-like A294T Frameshift at V378 Frameshift at T416 Frameshift at E471 Frameshift at E471 Frameshift at E471 Frameshift at E471 ins val 491 Walker A G512S Walker A R518W Walker A R518W G 522 W P560L P560L P560L P560L P56OR Splice at G593 Walker B S606P Frameshift at D649 R660W R660W Absent Not done S A Present S A Present T T Absent S D Decreased G T Absent N N Present R K Present Absent Y Y Not done D D Not done D D Absent Absent P R Decreased A A Not done Absent Absent Absent Absent Absent Absent Absent G G Absent R R Absent R R Decreased G E Absent P P Decreased P P Decreased P P Decreased P P Absent P P Absent Not done S S Absent Absent R R Absent R R Absent Not done Absent Absent Absent Present Absent Absent a CALD = cerebral ALD (5-15 years); AMN = adrenomyeloneuropathy; ALMD = adrenomyeloneuropathy with cerebral involvement; AD = Addison disease; AS = Asymptomatic. Login to comment
87 C, ALD fibroblasts (R152C mutation) immunostained with mAb2B4, showing normal ALDP immunoreactivity. Login to comment
175 Three missense mutations (S98L, N148S, and R152C) resulted in the synthesis of a stable but presumably nonfunctioning protein. Login to comment

[hide] ABCD1 mutations and the X-linked adrenoleukodystro... Hum Mutat. 2001 Dec;18(6):499-515. Kemp S, Pujol A, Waterham HR, van Geel BM, Boehm CD, Raymond GV, Cutting GR, Wanders RJ, Moser HW
ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations.
Hum Mutat. 2001 Dec;18(6):499-515., [PMID:11748843]

Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene, which encodes a peroxisomal ABC half-transporter (ALDP) involved in the import of very long-chain fatty acids (VLCFA) into the peroxisome. The disease is characterized by a striking and unpredictable variation in phenotypic expression. Phenotypes include the rapidly progressive childhood cerebral form (CCALD), the milder adult form, adrenomyeloneuropathy (AMN), and variants without neurologic involvement. There is no apparent correlation between genotype and phenotype. In males, unambiguous diagnosis can be achieved by demonstration of elevated levels of VLCFA in plasma. In 15 to 20% of obligate heterozygotes, however, test results are false-negative. Therefore, mutation analysis is the only reliable method for the identification of heterozygotes. Since most X-ALD kindreds have a unique mutation, a great number of mutations have been identified in the ABCD1 gene in the last seven years. In order to catalog and facilitate the analysis of these mutations, we have established a mutation database for X-ALD ( http://www.x-ald.nl). In this review we report a detailed analysis of all 406 X-ALD mutations currently included in the database. Also, we present 47 novel mutations. In addition, we review the various X-ALD phenotypes, the different diagnostic tools, and the need for extended family screening for the identification of new patients.

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164 X-ALD Mutations Identified in the ABCD1 Gene Allele Exon Mutation Protein Remark fs P42 1 125insC n.d. # fs P84 1 253insC n.d. # E90K 1 268G>A n.d. # S98L 1 293C>T Present S98L 1 293C>T Present R104H 1 311G>A n.d. fs A112 1 337delC Absent # R113C 1 337C>T Present # R113P 1 338G>C n.d. # Q133X 1 397C>T Absent W137X 1 411G>A Absent P143S 1 427C>T n.d. S149N 1 446G>A Present R152S 1 454C>A n.d. R152C 1 454C>T Present R152L 1 455G>T Reduced # S161P 1 481T>C n.d. # R163P 1 488G>C n.d. Y174C 1 521A>G Absent Y174C 1 521A>G n.d. Q177X 1 529C>T Absent Y181C 1 542A>G n.d. fs Y181 1 544ins8bp n.d. # Q195X 1 583C>T n.d. # T198K 1 593C>A n.d. # fs S207 1 621del664bp Absent # SV207-8insAAS 1 622-23ins9bp n.d. # K217E 1 649A>G Present # P218T 1 652C>A n.d. V224E 1 671T>G n.d. # L229P 1 686T>C n.d. L229P 1 686T>C n.d. fs S235 1 706delCGTG n.d. # W242X 1 726G>A Absent G266R 1 796G>A n.d. G266R 1 796G>A n.d. R274W, R280C 1 820C>T, 838C>T n.d. # R285P 1 854G>C n.d. S290X 1 869C>A Absent # E291del 1 871-73delGAG Absent Y296C 1 887A>G n.d. Y296C 1 887A>G n.d. fs E300 IVS1 IVS1+1g>t n.d. # fs E300 IVS1 IVS1-1g>a n.d. # S315X 2 944C>A n.d. # K336M 2 1007A>T n.d. # G343D 2 1028G>A n.d. # R401Q 3 1202G>A Present R401Q 3 1202G>A Present K407X 3 1219A>T n.d. # E427del 4 1279-81delGAA n.d. # Q430X 4 1288C>T n.d. # R464X 4 1390C>T n.d. fs E471 5 1415delAG Absent fs E471 5 1415delAG Absent fs E471 5 1415delAG Absent fs E471 5 1415delAG Absent C511X 6 1533C>A n.d. # R518Q 6 1553G>A Absent fs G528 6 1586-90del Absent # fs Y532 6 1599delG Absent # P543L 6 1628C>T Absent P543L 6 1628C>T Absent fs Q544 6 1628-34duplicated n.d. # fs R545 IVS 6 IVS6+1g>c n.d. # R554H 7 1661G>A Absent fs Q556 7 1670delTG n.d. # (continued) replaced by a pyrimidine (C or T) or vice versa, and transitions, comprising the substitution of one purine by the other, or of one pyrimidine by the other. Login to comment
297 In case different missense mutations were found in a single amino acid residue, like R152S, R152C, R152P, and R152L, only one was counted. Login to comment

[hide] Komrower Lecture. Adrenoleukodystrophy: natural hi... J Inherit Metab Dis. 1995;18(4):435-47. Moser HW
Komrower Lecture. Adrenoleukodystrophy: natural history, treatment and outcome.
J Inherit Metab Dis. 1995;18(4):435-47., [PMID:7494402]

Abstract [show]
Our laboratory has identified nearly 2000 patients with X-linked adrenoleukodystrophy (ALD) and conducted therapeutic trials in groups of patients who represent the major phenotypes. We report recent results of dietary therapy with a mixture of glyceryl trioleate and glyceryl trierucate oil, also referred to as Lorenzo's Oil, in the asymptomatic and childhood cerebral phenotypes. Fifty-three patients started this therapy at a mean age of 7.5 years at a time when they were free of neurological symptoms. Although analysis of data is hampered by the lack of a concurrent control group, follow-up studies after 39 months of therapy suggest that subsequent neurological involvement was less frequent and less severe than anticipated from historical controls. Retrospective analysis of the effect of the oil in patients with the severe childhood cerebral phenotype indicates that there was a slight but statistically significant slowing of clinical progression and delay of death.

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No. Sentence Comment
29 Mutation Predicted consequence Phenotype a 1 310 C -4 T R104C AMN 2 420 G -4 A A140T Cer 3 454 C -4 T R152C Cer 4 545 G -4 C R182P Addis 5 692 G -4 C Addis 693-4 del GG Frameshift at AA 231 6 770 G -4 T G277W Cer 7 1166 G -4 A R389H AMN 8 I224 G -4 A Spl mutation at AA 408 AMN 9 1389 G --+ A R464 stop AMN 10 1411 ins A Frameshift at AA 470 AMN 11 1412-3 del AA Frameshift at AA 470 Cer 12 1415-6 del AG Frameshift at AA 472 Cer 13 1415-6 del AG Frarneshift at AA 472 Cer 14 1415-6 del AG Frameshift at AA 472 Addis 15 1415-6 del AG Frameshift at AA 472 AMN 16 t415-6 del AG Frameshift at AA 472 AMN 17 1415-6 del AG Frameshift at AA 472 Cer 18 1534 G -4 A G512S Cer 19 1698 T -4 A M567K AMN 20 t817 C -4 T $604F Addis 1548 G -4 A L516L 21 1850 G -+ A R617H AMN 22 1978 G -4 A R660W AMN ~Cer=childhoodcerebralALD; Addis=Addisondisease the multiple binding sites on bovine albumin for shorter-chain fatty acids, there is only a single binding site for C26:0. Login to comment

[hide] Identification of seven novel mutations in ABCD1 b... Hum Mutat. 2005 Feb;25(2):222. Montagna G, Di Biase A, Cappa M, Melone MA, Piantadosi C, Colabianchi D, Patrono C, Attori L, Cannelli N, Cotrufo R, Salvati S, Santorelli FM
Identification of seven novel mutations in ABCD1 by a DHPLC-based assay in Italian patients with X-linked adrenoleukodystrophy.
Hum Mutat. 2005 Feb;25(2):222., [PMID:15643618]

Abstract [show]
We report the molecular findings in 14 patients (12 families) with X-linked adrenoleukodystrophy (X-ALD, MIM# 300100), a well-defined peroxisomal disorder attributed to mutations in the ABCD1 gene on chromosome Xq28. With the aims of determining the spectrum of mutations and developing an efficient molecular genetic test for analysis of at-risk women whose carrier status is unknown, and to offer molecular confirmation of their status to obligate heterozygotes, regardless of their clinical status, we carried out molecular screening by setting up a denaturing high-performance liquid chromatography (DHPLC)-based protocol. We identified eleven hemizygous base changes in ABCD1, including seven new mutations (c.145underscore;146ins4, c.264C>G, c.919C>T, c.994C>T, c.1027G>A, c.1508T>C, and c.1540A>C, resulting in the p.Pro193fs, p.Cys88Trp, p.Gln307X, p.Gln332X, p.Gly343Ser, p.Leu503Pro, and p.Ser514Arg changes, respectively). Adding new variants to the repertoire of ABCD1 mutations in X-ALD, our data provide an efficient, cost-effective, and reliable DHPLC detection protocol for mutation screening of X-ALD families.

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87 Additional mutations identified in this study (c. 454C>T, c.542A>G, c.1415_1416del2, and c.1661G>A, resulting respectively in the variants p.Arg152Cys, p.Tyr181Cys, p.Glu471fs, and p.Arg554His), each found in one family, have already been listed in the X-ALD mutation database (http://www.x-ald.nl). Login to comment
95 Summary of Mutations in ABCD1 (RefSeq: NM_000033.2) Identified in this Study ABCD1 gene cDNA level Protein level Exon 1 c.145_146ins4 p.Pro49fs Exon 1 c.264C>G p.Cys88Trp Exon 1 c. 454C>T p.Arg152Cys Exon 1 c.542A>G p.Tyr181Cys Exon 2 c.919C>T p.Gln307X Exon 2 c.994C>T p.Gln332X Exon 2 c.1027G>A p.Gly343Ser Exon 5 c.1415_1416del2 p.Glu471fs Exon 6 c.1508T>C p.Leu503Pro Exon 6 c.1540A>C p.Ser514Arg Exon 7 c.1661G>A p.Arg554His Novel variants are in bold. Login to comment

[hide] Adult-onset dementia with prominent frontal lobe d... J Neurol. 2003 Oct;250(10):1253-4. Larner AJ
Adult-onset dementia with prominent frontal lobe dysfunction in X-linked adrenoleukodystrophy with R152C mutation in ABCD1 gene.
J Neurol. 2003 Oct;250(10):1253-4., [PMID:14586615]

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0 J Neurol (2003) 250:-1254 DOI 10.1007/s00415-003-0172-7 A. J. Larner Adult-onset dementia with prominent frontal lobe dysfunction in X-linked adrenoleukodystrophy with R152C mutation in ABCD1 gene Received: 24 March 2003 Accepted: 14 May 2003 Sirs: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with various clinical phenotypes, dependent on the age of presentation [6]. Login to comment
11 Analysis of the X-ALD gene,ATP-binding cassette (ABCD1) [3, 4], showed a missense mutation at codon 454 in exon 1 (454C>T), predicting the substitution R152C in the transmembrane domain of ALD protein. Login to comment
29 Previous reports of R152C mutation have appeared [3, 4] but without details of clinical phenotype. Login to comment
1 J. Larner Adult-onset dementia with prominent frontal lobe dysfunction in X-linked adrenoleukodystrophy with R152C mutation in ABCD1 gene Received: 24 March 2003 Accepted: 14 May 2003 Sirs: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with various clinical phenotypes, dependent on the age of presentation [6]. Login to comment
12 Analysis of the X-ALD gene,ATP-binding cassette (ABCD1) [3, 4], showed a missense mutation at codon 454 in exon 1 (454C>T), predicting the substitution R152C in the transmembrane domain of ALD protein. Login to comment
30 Previous reports of R152C mutation have appeared [3, 4] but without details of clinical phenotype. Login to comment

[hide] Mutational analysis of patients with X-linked adre... Hum Mutat. 1995;6(2):104-15. Kok F, Neumann S, Sarde CO, Zheng S, Wu KH, Wei HM, Bergin J, Watkins PA, Gould S, Sack G, et al.
Mutational analysis of patients with X-linked adrenoleukodystrophy.
Hum Mutat. 1995;6(2):104-15., [PMID:7581394]

Abstract [show]
Adrenoleukodystrophy (ALD) is an X-linked neurodegenerative disorder characterized by elevated very long chain fatty acid (VLCFA) levels, reduced activity of peroxisomal VLCFA-CoA ligase, and variable phenotypic expression. A putative gene for ALD was recently identified and surprisingly encodes a protein (ALDP) that belongs to a family of transmembrane transporters regulated or activated by ATP (the ABC proteins). We have examined genomic DNA from ALD probands for mutations in the putative ALD gene. We detected large deletions of the carboxyl-terminal portion of the gene in 4 of 112 probands. Twenty-five of the ALD probands whose ALD genes appeared normal by Southern blot analysis were surveyed for mutations by Single Strand Conformation Polymorphism (SSCP) procedures and DNA sequence analysis. SSCP variants were detected in 22 probands and none in 60 X-chromosomes from normal individuals. Mutations were detected in all of the ALD probands. The mutations were distributed throughout the gene and did not correlate with phenotype. Approximately half were non-recurrent missense mutations of which 64% occurred in CpG dinucleotides. There was a cluster of frameshift mutations in a small region of exon 5, including an identical AG deletion in 7 unrelated probands. These data strongly support the supposition that mutations in the putative ALD gene result in ALD.

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131 3' deletion 3' deletion 3' deletion 3' deletion R104C A141T R152C R182P Frameshift at AA 231 G277W R389H Spl mutation at AA 408 Q466 stop Frameshift at AA 470 Frameshift at AA 470 Frameshift at AA 472 Frameshift at AA 472 Frameshift at AA 472 Frameshift at AA 472 Frameshift at AA 472 Frameshift at AA 472 Frameshift at AA 472 G512S M566K S606L L516L R617H R660W - - Exons 3-10 Exons 7-10 Exons 8-10 Exons 7-10 33 Anglos 5 Scott 8 Anglos 7 Anglos 11 Jewish 36 Irish 51 Italian 37 Filipino 28 Anglos 23 Anglos 11 Anglos 8 Anglos 40 Italian 22 German 4 Anglos 5 black 8 Anglos 31 Anglos 10 Anglos 28 Anglos 22 Italian 8 German 35 German 7 Hispanic 28 German 24 Anglos 18 Jewish 9 Hispanic AMNa C E R ~ Cer Add' Cer AMN AMN AMN AMN Cer Cer Cer Add AMN AMN Cer Cer Cer AMN Add AMN AMN Cer AMN Cer AMN AMN AMN 5 Cer,AMN,Add 4 Cer,AMN 1 Cer 5 Cer,AMN,Add 1 4 2 1 2 2 5 Adopted 5 2 15 1 13 2 2 1 Cer AMN AMN,Add AMN Cer,AMN Cer,AMN Cer,AMN,Add ? Login to comment