ABCMdb

ABCD1 p.Arg518Trp

ClinVar:	c.1553G>A , p.Arg518Gln D , Pathogenic c.1552C>T , p.Arg518Trp 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 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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59 Twenty-nine different mutations were found, and five of them were present in more than one family (S98L, R518W, and R660W in two families, and 1801 delAG and P560L in four families each). Login to comment
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
102 Variation in the immunoreactivity of the ALD mutant protein was observed for two mutations, P560L and R518W: immunoreactivity of mutant protein P560L was markedly decreased in fibroblasts and peripheral white blood cells from patients 69, 5, and 37 and was completely absent in patient 13. Login to comment
104 Similarly, ALDP immunoreactivity of mutant protein R518W was markedly decreased in fibroblasts from patient 76 and completely absent in fibroblasts from another patient (73) with the same mutation. Login to comment
134 Exceptions are a dinucleotide deletion (del 1801-1802) and P560L missense mutation, which were both observed in four kindreds, and S98L, R518W, and R660W missense mutations, which were each observed in two kindreds. Login to comment
140 In all cases, only one alteration was found, and except for the S98L, R518W, P560L, and R660W mutations, these alterations differed from each other. Login to comment
142 The R518W mutation occurred as a de novo mutation in one ALD patient, and the R518W and P560L mutations were not observed in 100 normal X chromosomes. Login to comment
144 Four missense mutations (G512S, R518W, G522W, and S606P) were found in the ATP-binding domain. Login to comment
173 Four missense mutations (S108W, P263L, R518W, and P560L) resulted in decreased ALDP immunoreactivity reflecting likely instability and/or partial deficiency in the peroxisomal targeting of ALDP. 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
58 Twenty-nine different mutations were found, and five of them were present in more than one family (S98L, R518W, and R660W in two families, and 1801 delAG and P560L in four families each). 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

[hide] Identification of novel SNPs of ABCD1, ABCD2, ABCD... Neurogenetics. 2011 Feb;12(1):41-50. Epub 2010 Jul 27. Matsukawa T, Asheuer M, Takahashi Y, Goto J, Suzuki Y, Shimozawa N, Takano H, Onodera O, Nishizawa M, Aubourg P, Tsuji S
Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes.
Neurogenetics. 2011 Feb;12(1):41-50. Epub 2010 Jul 27., [PMID:20661612]

Abstract [show]
Adrenoleukodystrophy (ALD) is an X-linked disorder affecting primarily the white matter of the central nervous system occasionally accompanied by adrenal insufficiency. Despite the discovery of the causative gene, ABCD1, no clear genotype-phenotype correlations have been established. Association studies based on single nucleotide polymorphisms (SNPs) identified by comprehensive resequencing of genes related to ABCD1 may reveal genes modifying ALD phenotypes. We analyzed 40 Japanese patients with ALD. ABCD1 and ABCD2 were analyzed using a newly developed microarray-based resequencing system. ABCD3 and ABCD4 were analyzed by direct nucleotide sequence analysis. Replication studies were conducted on an independent French ALD cohort with extreme phenotypes. All the mutations of ABCD1 were identified, and there was no correlation between the genotypes and phenotypes of ALD. SNPs identified by the comprehensive resequencing of ABCD2, ABCD3, and ABCD4 were used for association studies. There were no significant associations between these SNPs and ALD phenotypes, except for the five SNPs of ABCD4, which are in complete disequilibrium in the Japanese population. These five SNPs were significantly less frequently represented in patients with adrenomyeloneuropathy (AMN) than in controls in the Japanese population (p=0.0468), whereas there were no significant differences in patients with childhood cerebral ALD (CCALD). The replication study employing these five SNPs on an independent French ALD cohort, however, showed no significant associations with CCALD or pure AMN. This study showed that ABCD2, ABCD3, and ABCD4 are less likely the disease-modifying genes, necessitating further studies to identify genes modifying ALD phenotypes.

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84 Interestingly, the five previously described SNPs (rs17782508, rs2301345, rs4148077, rs4148078, and rs3742801) that are in complete linkage disequilibrium were significantly less frequently represented in the patients with Japanese AMN than in the controls in the Japanese population (p=0.0468), whereas Table 2 Identified ABCD1 mutations: mutations of ABCD1 that result in amino acid substitutions or in-frame deletions Patient number Phenotype Mutation of ABCD1 Effect of mutation of ABCD1 Position of mutation 13 CCALD 709C>T S108L Loop1 14 CCALD 709C>T S108L Loop1 15 CCALD 829A>G N148S TM2 16 CCALD 1026A>G N214D TM3 17 CCALD 1182G>A G266R Between TM4 and EAA-like 18 CCALD 1324T>Ca L313P Between EAA-like and TM5 19 CCALD 1938C>T R518W Walker A 20 CCALD 1939G>A R518Q Walker A 21 CCALD 2017A>G Q544R Between Walker A and Cons 22 CCALD 2017A>G Q544R Between Walker A and Cons 23 CCALD 2065C>T P560L Between Walker A and Cons 24 CCALD 2065C>T P560L Between Walker A and Cons 25 CCALD Del. 2145-2156 Del. HILQ587-590 Between Walker A and Cons 26 AdultCer Del. 1257-1259 Del.E291 EAA-like 27 AdultCer 2005T>C F540S Between Walker A and Cons 28 AdultCer 2358C>T R660W C-terminal to Walker B 29 AdultCer 2385C>A H667N C-terminal to Walker B 30 AMN-Cer 1146A>C T254P TM4 31 AMN 636C>T P84S TM1 32 AMN 709C>T S108L Loop1 33 AMN 1182G>A G266R Between TM4 and EAA-like 34 AMN 1197G>A E271K Between TM4 and EAA-like 35 AMN 1215G>Aa G277R Between TM4 and EAA-like 36 AMN 1255C>G S290W EAA-like 37 AMN 1581C>T R401W Between TM6 and Walker A 38 AMN 2233C>A A616D Cons 39 AMN 2385C>A H667N C-terminal to Walker B 40 Asymptomatic 2211G>A E609K Cons Amino acid residue numbers in ALDP are based on Mosser et al. [1]. Login to comment

[hide] Homo- and heterodimerization of peroxisomal ATP-bi... J Biol Chem. 1999 Nov 12;274(46):32738-43. Liu LX, Janvier K, Berteaux-Lecellier V, Cartier N, Benarous R, Aubourg P
Homo- and heterodimerization of peroxisomal ATP-binding cassette half-transporters.
J Biol Chem. 1999 Nov 12;274(46):32738-43., [PMID:10551832]

Abstract [show]
Mammalian peroxisomal proteins adrenoleukodystrophy protein (ALDP), adrenoleukodystrophy-related protein (ALDRP), and 70-kDa peroxisomal protein (PMP70) belong to the superfamily of ATP-binding cassette (ABC) transporters. Unlike many ABC transporters that are single functional proteins with two related halves, ALDP, ALDRP, and PMP70 have the structure of ABC half-transporters. The dysfunction of ALDP is responsible for X-linked adrenoleukodystrophy (X-ALD), a neurodegenerative disorder in which saturated very long-chain fatty acids accumulate because of their impaired peroxisomal beta-oxidation. No disease has so far been associated with mutations of adrenoleukodystrophy-related or PMP70 genes. It has been proposed that peroxisomal ABC transporters need to dimerize to exert import functions. Using the yeast two-hybrid system, we show that homo- as well as heterodimerization occur between the carboxyl-terminal halves of ALDP, ALDRP, and PMP70. Two X-ALD disease mutations located in the carboxyl-terminal half of ALDP affect both homo- and heterodimerization of ALDP. Co-immunoprecipitation demonstrated the homodimerization of ALDP, the heterodimerization of ALDP with PMP70 or ALDRP, and the heterodimerization of ALDRP with PMP70. These results provide the first evidence of both homo- and heterodimerization of mammalian ABC half-transporters and suggest that the loss of ALDP dimerization plays a role in X-ALD pathogenesis.

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152 In contrast, the R591Q disease mutation, which alters the dimerization of ALDP in the yeast two-hybrid assays, does not lead to ALDP unstability in vivo. Login to comment
154 This is supported by the observation that several ALDP missense mutations (in particular R518W and P560L) can lead to either a normal, decreased level or absence of ALDP in ALD fibroblasts.4 The specific carboxyl-terminal subdomain region of ALDP responsible for dimerization could not be defined. Login to comment
153 This is supported by the observation that several ALDP missense mutations (in particular R518W and P560L) can lead to either a normal, decreased level or absence of ALDP in ALD fibroblasts.4 The specific carboxyl-terminal subdomain region of ALDP responsible for dimerization could not be defined. Login to comment

[hide] Two novel missense mutations in the ATP-binding do... Clin Genet. 1997 May;51(5):322-5. Imamura A, Suzuki Y, Song XQ, Fukao T, Uchiyama A, Shimozawa N, Kamijo K, Hashimoto T, Orii T, Kondo N
Two novel missense mutations in the ATP-binding domain of the adrenoleukodystrophy gene: immunoblotting and immunocytological study of two patients.
Clin Genet. 1997 May;51(5):322-5., [PMID:9212180]

Abstract [show]
Two novel missense mutations, 1939G to A (R518Q) and 2017A to G (Q544R) were identified in Japanese patients with adrenoleukodystrophy (ALD). They are located in exon 6, which encodes part of the putative adenosine triphosphate binding domain of ALD protein. The ALD protein carrying the R518Q mutation was undetectable in fibroblasts, by immunoblot and immunofluorescence analysis, while the Q544R mutation had no apparent effect on the stability and localization of the ALD protein, but is expected to affect its function.

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63 G512S, R518W and G522W (Feigenbaum et al. 1996). Login to comment

[hide] Molecular characterization of 21 X-ALD Portuguese ... Mol Genet Metab. 2002 May;76(1):62-7. Guimaraes CP, Lemos M, Sa-Miranda C, Azevedo JE
Molecular characterization of 21 X-ALD Portuguese families: identification of eight novel mutations in the ABCD1 gene.
Mol Genet Metab. 2002 May;76(1):62-7., [PMID:12175782]

Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder. The gene associated with X-ALD, ABCD1, encodes a peroxisomal ATP-binding cassette half-transporter. In this study, we describe the molecular characterization of 21 affected Portuguese families. The complete coding region of the ABCD1 gene was amplified by reverse transcription polymerase chain reaction (RT-PCR) or genomic PCR. After conformation-sensitive gel electrophoresis analysis, fragments with a conformational heteroduplex pattern were sequenced. Using this strategy, we have identified 14 missense mutations, two nonsense mutations, two splicing site defects, and three small deletions, two of them resulting in frameshifts. Eight of the genetic alterations characterized in this study are novel. The levels of the ABCD1 transcript as well as the levels of ALDP in cultured skin fibroblasts of male probands were also determined in most cases. The levels of the ABCD1 transcript in one patient (corresponding to a nonsense mutation) were below the detection limit of Northern-blotting analysis. ALDP was found at normal levels in only three patients, absent in five (corresponding to a double missense, two nonsense, and two frameshift mutations), and decreased in all the others.

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66 Type of genetic alteration Exon RT-PCR fragmenta Nucleotide change Amplicon usedb /RFLP associatedc ALDP (WB) ABCD1 mRNA (NB) References Missense 1 S103R 1 F2 c.309C > G ALDe1A/þCfoI Diminished Detectable [19] 2 S108W 1 - c.323C > G ALDe1B/þRleAI Not done Not done [18] 3 S108L 1 - c.323C > T - Normal Not done [20] 4 L114P 1 F2 c.341T > C ALDe1B/ÀEcoRII Diminished Detectable Novel mutation 5 ½R236H; G512S 1 F3 [c.707G > A; ALDe1C/þNcoI Novel mutation 6 F6 c.1534G > A] ALDe6/þPstI Not detectable Not done [16,17] 6 G266R 1 F3 c.796G > A - Normal Detectable [21] 7 R518W 6 F6 c.1552C > T ALDe6/ÀHpaII Diminished Detectable [22] 8 R518Q 6 F6 c.1153G > A ALDe6/ÀBamHI Diminished Not done [23] 9 R545W 6 - c.1633A > T ALDe6/þTspRI Not done Not done Novel mutation 10 R591W 7 F7 c.1171C > T ALDe7/ÀAciI Normal Not done [24] 11 L655P 9 F8 c.1964T > C ALDe8/9/ÀSapId Diminished Detectable Novel mutation 12 R660W 9 F7/F8 c.1978C > T ALDe8/9/þBsrI Diminished Detectable [16,17,25] 13 H667L 10 F8 c.2000A > T ALDe10/þDdeId Diminished Detectable Novel mutation Nonsense 14 Q574X 7 F6 c.1720C > T ALDe7/ÀAlwNI Not detectable Detectable Novel mutation 15 W601X 8 F7 c.1802G > A ALDe8/9/ÀBsrI Not detectable Not detectable [9] Frameshift 16 fs G298 1 F3 [c.893delG; c.894C > T] ALDe1C/ÀNlaIV Not detectable Detectable Novel mutation 17, 18 fs E472 5 F5 c.1415-1416delAG - Not detectable Detectable [21,26,27] Microdeletion 19 F175del 1 F2 c.522-524delCTT d Diminished Detectable Novel mutation Splicing defect 20 Splicing IVS1 - c.900G > A - Not done Not done [10] 21 Splicing IVS7 - c.1760+1G > A - Not done Not done [18] Polymorphism 1, 5 F673F 8 F8 c.2019C > T ÀTaqI - - [28] 1, 2, 5, 11, 13 30 UTR F8 - ÀDrdI - - [27] a RT-PCR fragment (defined according to [10]) which shows heteroduplex molecules in a CSGE analysis. Login to comment

[hide] Female carriers of X-chromosomal adrenoleukodystro... J Neurol. 2010 Aug;257(8):1394-5. Epub 2010 Mar 2. Guettsches AK, Kuechler A, Gal A, Schmitz W, Tegenthoff M, Vorgerd M
Female carriers of X-chromosomal adrenoleukodystrophy: a major differential diagnosis in progressive myelopathy.
J Neurol. 2010 Aug;257(8):1394-5. Epub 2010 Mar 2., [PMID:20195870]

Abstract [show]
Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are allelic X-chromosomal disorders of peroxisomal lipid metabolism due to mutations of the ABCD1-gene, leading, respectively, to leukoencephalopathy or myeloneuropathy in male patients. We report a family with two symptomatic carriers in subsequent generations who both suffer from symptoms of an AMN. In both patients, molecular genetic testing revealed a heterozygous c.1552C>T-transition (p.Arg518Trp) in exon 6 of ABCD1. Our observations underline the importance of identifying such symptomatic ALD carriers.

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2 In both patients, molecular genetic testing revealed a heterozygous c.1552C[T-transition (p.Arg518Trp) in exon 6 of ABCD1. Login to comment
22 In I.1, II.2, and II.3, genetic analysis of ABCD1 revealed a heterozygote C[T-transition (c.1552C[T) in exon 6 (Table 1), which is expected to result in the replacement of an evolutionary conserved arginine residue by a tryptophane (p.Arg518Trp). Login to comment
23 In I.1, II.2, and II.3, genetic analysis of ABCD1 revealed a heterozygote C[T-transition (c.1552C[T) in exon 6 (Table 1), which is expected to result in the replacement of an evolutionary conserved arginine residue by a tryptophane (p.Arg518Trp). Login to comment

[hide] Identification of mutations in the putative ATP-bi... J Clin Invest. 1994 Aug;94(2):516-20. Fanen P, Guidoux S, Sarde CO, Mandel JL, Goossens M, Aubourg P
Identification of mutations in the putative ATP-binding domain of the adrenoleukodystrophy gene.
J Clin Invest. 1994 Aug;94(2):516-20., [PMID:8040304]

Abstract [show]
The recently identified adrenoleukodystrophy (ALD) gene is predicted to encode a peroxisomal protein of 745 amino acids that includes one domain for ATP-binding, termed nucleotide-binding fold (NBF). To determine whether mutations occur in the putative NBF of ALD protein, we analyzed by denaturing gradient gel electrophoresis (DGGE) exon 6 and 8 that encode most part of this domain in 50 ALD patients. Four amino acid substitutions, three frameshift mutations leading to premature termination signal, and a splicing mutation were identified. These amino acid substitutions occurred at residues highly conserved in other ATP-binding cassette (ABC) proteins. In addition, a nonsense mutation was detected in exon 4.

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48 Asterisks indicate the posi- *l I U13 | tion of the four missense mutations in ALD protein (ALDP): R518W substitution occurs at the same amino acid position as in the CFTR mutant S1255P, and S606L at the same position as in the S5491 or S549R CFTR mutants; R617C and R617H have no equivalents in CFTR mutants. Login to comment
81 This mutation (Arg 518 -+ Trp or R518W in the single letter amino acid code) (Fig. 3) causes a nonconservative change between a charged and strongly polar (basic) amino acid and a hydrophobic nonpolar amino acid (Fig. 1). Login to comment
97 These three missense mutations and the R518W were not observed in 100 normal X chromosomes, strongly suggesting that they are deleterious. Login to comment
109 G Trp - G7 518 lie \t-519 nt 1943 R518W AGCT nt1935 _ / T Phe ~C_ 517 G. ml -> G Gly _.__ A 518 = T- _m C Ser - 519 nt 943 1 937delC Figure 3. Login to comment
110 Partial nucleotide sequence of exon 6 in control, in the AMN patient with the R518W mutation and in the abnormal allele of the heterozygous mother with the 1937delC mutation. Login to comment
138 The chloride channel activity of the CFTR mutant S 1255P, which involves the same amino acid position in the NBF as in the ALD mutant R518W, is less sensitive to ATP stimulation (24) and the MDR mutants K433M or K1076M within the same Walker motif are unable to hydrolyze ATP (25). Login to comment
145 Mutations Detected in the ALD Gene Name Nucleotide change Effect on coding sequence Exon Clinical phenotype R464X C - T at 1776 Arg - Stop at 464 4 AMN* 1937delC Deletion of C at 1937 Frameshift 6 cerebral ALD R518W CT at 1938 Arg-Trpat 518 6 AMN 2020 + I G - A G - A at 2020 + 1 5' splice signal Intron 6 ACMN2 2177delTA Deletion of TA at 2177 Frameshift 8 cerebral ALD S606L C - T at 2203 Ser - Leu at 606 8 Addison 2204delG Deletion of G at 2204 Frameshift 8 Addison R617C C - T at 2235 Arg - Cys at 617 8 cerebral ALD R617H G - A at 2236 Arg - His at 617 8 ACMN * Adrenomyeloneuropathy; tadrenomyeloneuropathy with cerebral involvement. Login to comment

[hide] Eight novel mutations in the ABCD1 gene and clinic... World J Pediatr. 2015 Nov;11(4):366-73. doi: 10.1007/s12519-015-0044-0. Epub 2015 Oct 11. Chu SS, Ye J, Zhang HW, Han LS, Qiu WJ, Gao XL, Gu XF
Eight novel mutations in the ABCD1 gene and clinical characteristics of 25 Chinese patients with X-linked adrenoleukodystrophy.
World J Pediatr. 2015 Nov;11(4):366-73. doi: 10.1007/s12519-015-0044-0. Epub 2015 Oct 11., [PMID:26454440]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by mutations in the adenosine triphosphate-binding cassette D1 (ABCD1) gene. This study aimed to retrospectively investigate the clinical characteristics of 25 patients with X-ALD including members of large pedigrees, to analyze ABCD1 gene mutations, the effect of gene novel variants on ALD protein (ALDP) structure and function, and to expand gene mutation spectrum of Chinese patients. METHODS: Twenty-five male patients diagnosed with X-ALD were enrolled in this study. The clinical characteristics of the patients were retrospectively summarized by reviewing medical records or telephone consultation. ABCD1 gene mutations were analyzed. The pathogenicity of novel missense variants was analyzed using cobalt constraint-based multiple protein alignment tool, polymorphism phenotyping, sorting intolerant from tolerant, Align-Grantham variation and Grantham deviation, and Swiss-Program Database Viewer 4.04 software, respectively. RESULTS: Childhood cerebral form ALD (CCALD) is the most common phenotype (64%) in the 25 patients with X-ALD. The progressive deterioration of neurological and cognitive functions is the main clinical feature. The demyelination of the brain white matter and elevated plasma very long chain fatty acids (VLCFAs) were found in all patients. Different phenotypes were also presented within family members of the patients. Twenty-two different mutations including 8 novel mutations in the ABCD1 gene were identified in the 25 patients. Of the mutations, 63.6% were missense mutations and 34.8% located in exon 1. The amino acid residues of three novel missense mutations in eight species were highly conserved, and were predicted to be "probably" damaging to ALDP function. The other five novel mutations were splice, nonsense, deletion or duplication mutations. CONCLUSIONS: CCALD is the most common phenotype (64%) in our patients with X-ALD. Eight novel mutations in the ABCD1 gene identified are disease-causing mutations. Brain magnetic resonance imaging and plasma VLCFA determination should be performed for the patients who present with progressive deterioration of neurological development.

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111 However, some X-ALD males remain asymptomatic and one-third of heterozygous women remain free of clinical symptoms during their Patient number Exon Nucleotide change Amino acid change Protein localization References P1 2 c.1017G>T p.Trp339Cys TMD Novel P2 8 c.1850G>A p.Arg617His NBD Fanen et al, 1994[12] P4 1 c.892G>C p.Gly298Arg TMD Novel P5, P6 5 c.1415_16delAG p.Gln472Argfs*83 TMD to NBD Barcelo et al, 1994[13] P7 1 c.532C>T p.Gln178* TMD Novel P8 1 c.473T>C p.Leu158Pro TMD The peroxisomal diseases laboratory (unpublished) P10 6 c.1552C>T p.Arg518Trp NBD Fanen et al, 1994[12] P11 3 c.1202G>A p.Arg401Gln TMD to NBD Fuchs et al, 1994[14] P12 1 c.887A>G p.Tyr296Cys TMD Takano et al, 1999[15] P13 1 c.893G>A p.Gly298Asp TMD Lachtermacher et al, 2000[16] P14 1 c.310C>T p.Arg104Cys TMD Kok et al, 1995[17] P15 IVS 8 c.1866-10G>A p.Pro623fs* NBD Kemp et al, 1995[18] P16 5 c.1428C>A p.Cys476* NBD Novel P17 5 c.1421T>C p.Ile474Thr NBD Shimozawa et al, 2011[19] P18 6 c.1538A>G p.Lys513Arg NBD Piti&#e9;-Salp&#e9;tri&#e8;re Hospital (unpublished) P19 1 c.310C>T p.Arg104Cys TMD Kok et al, 1995[17] P20 6 c.1544C>A p.Ser515Tyr NBD Novel P21 2 c.901-1G>A p.Val301fs* TMD Kemp et al, 2001[20] P22 2 c.974T>C p.Leu325Pro TMD The peroxisomal diseases laboratory (unpublished) P23 3 c.1182delG p.Ala395Leufs*15 TMD to NBD Novel P24 1 c.424delC p.Leu142Serfs*56 TMD Novel P25 7 c.1759_1761dup p.Ile588His NBD Novel Table 2. Login to comment