ABCMdb

ABCD1 p.Arg389His

ClinVar:	c.1165C>G , p.Arg389Gly 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 (85%), L: D (95%), M: D (91%), N: D (95%), P: D (95%), Q: D (95%), S: D (91%), 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: 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] 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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235 For example, a family has been identified in The Netherlands with a missense mutation, R389H, and normal levels of ALDP. 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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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] 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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47 ALD point mutations (R389H, R401Q, P484R, and R591Q) were individually introduced into pGBT- and pLEX-hALDPc by site-directed mutagenesis using "overlap extension PCR" with Pfu polymerase (Stratagene) and appropriate primers (25). Login to comment
72 These mutations (R389H, R401Q, P484R, and R591Q) were generated as described above and tested in two-hybrid assays. Login to comment
73 The P484R mutation leads to a decreased amount of ALDP in patient fibroblasts,3 whereas the three other mutations have no effect on ALDP stability in vivo (28-31). Login to comment
74 Our results show that the mutations R389H and R401Q had no effect on the interactions of hALDPc with itself (Fig. 2A, rows 1, 3, and 5), mALDRPc (Fig. 2B, rows 1, 3, and 5), or hPMP70c (Fig. 2C, rows 1, 3, and 5). Login to comment
90 B and C, interactions of wild type and mutated (R389H, R401Q, P484R, and R591Q) ALDPc with mALDRPc and hPMP70c. Login to comment
95 A, HF7c yeast strains expressing wild type or mutated (R389H, R401Q, P484R, and R591Q) ALDPc fused to Gal4-BD were analyzed for histidine auxotrophy (left panel, medium with histidine; right panel, medium without histidine). Login to comment
46 ALD point mutations (R389H, R401Q, P484R, and R591Q) were individually introduced into pGBT- and pLEX-hALDPc by site-directed mutagenesis using "overlap extension PCR" with Pfu polymerase (Stratagene) and appropriate primers (25). Login to comment
71 These mutations (R389H, R401Q, P484R, and R591Q) were generated as described above and tested in two-hybrid assays. Login to comment
89 B and C, interactions of wild type and mutated (R389H, R401Q, P484R, and R591Q) ALDPc with mALDRPc and hPMP70c. Login to comment
94 A, HF7c yeast strains expressing wild type or mutated (R389H, R401Q, P484R, and R591Q) ALDPc fused to Gal4-BD were analyzed for histidine auxotrophy (left panel, medium with histidine; right panel, medium without histidine). Login to comment
45 ALD point mutations (R389H, R401Q, P484R, and R591Q) were individually introduced into pGBT- and pLEX-hALDPc by site-directed mutagenesis using "overlap extension PCR" with Pfu polymerase (Stratagene) and appropriate primers (25). Login to comment
70 These mutations (R389H, R401Q, P484R, and R591Q) were generated as described above and tested in two-hybrid assays. Login to comment
88 B and C, interactions of wild type and mutated (R389H, R401Q, P484R, and R591Q) ALDPc with mALDRPc and hPMP70c. Login to comment
93 A, HF7c yeast strains expressing wild type or mutated (R389H, R401Q, P484R, and R591Q) ALDPc fused to Gal4-BD were analyzed for histidine auxotrophy (left panel, medium with histidine; right panel, medium without histidine). Login to comment

[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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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] Conservation of targeting but divergence in functi... Biochem J. 2011 Jun 15;436(3):547-57. Zhang X, De Marcos Lousa C, Schutte-Lensink N, Ofman R, Wanders RJ, Baldwin SA, Baker A, Kemp S, Theodoulou FL
Conservation of targeting but divergence in function and quality control of peroxisomal ABC transporters: an analysis using cross-kingdom expression.
Biochem J. 2011 Jun 15;436(3):547-57., [PMID:21476988]

Abstract [show]
ABC (ATP-binding cassette) subfamily D transporters are found in all eukaryotic kingdoms and are known to play essential roles in mammals and plants; however, their number, organization and physiological contexts differ. Via cross-kingdom expression experiments, we have explored the conservation of targeting, protein stability and function between mammalian and plant ABCD transporters. When expressed in tobacco epidermal cells, the mammalian ABCD proteins ALDP (adrenoleukodystrophy protein), ALDR (adrenoleukodystrophy-related protein) and PMP70 (70 kDa peroxisomal membrane protein) targeted faithfully to peroxisomes and P70R (PMP70-related protein) targeted to the ER (endoplasmic reticulum), as in the native host. The Arabidopsis thaliana peroxin AtPex19_1 interacted with human peroxisomal ABC transporters both in vivo and in vitro, providing an explanation for the fidelity of targeting. The fate of X-linked adrenoleukodystrophy disease-related mutants differed between fibroblasts and plant cells. In fibroblasts, levels of ALDP in some 'protein-absent' mutants were increased by low-temperature culture, in some cases restoring function. In contrast, all mutant ALDP proteins examined were stable and correctly targeted in plant cells, regardless of their fate in fibroblasts. ALDR complemented the seed germination defect of the Arabidopsis cts-1 mutant which lacks the peroxisomal ABCD transporter CTS (Comatose), but neither ALDR nor ALDP was able to rescue the defect in fatty acid beta-oxidation in establishing seedlings. Taken together, our results indicate that the mechanism for trafficking of peroxisomal membrane proteins is shared between plants and mammals, but suggest differences in the sensing and turnover of mutant ABC transporter proteins and differences in substrate specificity and/or function.

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153 Approximately 60% of X-ALD ABCD1 mutations are missense mutations, 65% of which result in no detectable ALDP, based on IF (immunofluorescence), indicating that they affect protein Table 1 Quantification of ALDP levels in X-ALD fibroblasts ALDP Mutation IF Immunoblot (% of control) p.Arg74Trp Absent 7.5 + - 0.6 p.Arg104Cys Reduced 35 + - 3.0 p.Ser149Asn Present 77 + - 3.0 p.Asp194His Present 60 + - 13.6 p.Leu220Pro Reduced 21.8 + - 5.4 p.Arg389His Present 40.6 + - 3.6 p.Arg554His Absent 1.0 + - 0.5 p.Ser606Leu Present 25 + - 1.5 p.Glu609Gly Absent 2.1 + - 1.3 p.Glu609Lys Absent 1.8 + - 0.9 p.Ala616Thr Absent 4.3 + - 1.7 p.Leu654Pro Absent 1.5 + - 1.3 p.Arg660Trp Absent 1.6 + - 0.8 p.His667Asp Absent 2.9 + - 1.0 p.Arg113fs Absent - Figure 3 Interaction of mammalian ABCD proteins with Arabidopsis Pex19 in vivo Tobacco plants stably expressing CFP-SKL were co-transfected with 35S::ABCD-YFP fusions andNLS-Pex19constructs.Leafepidermalcellswereimagedusingconfocalmicroscopy:(A-D) ALDP-YFP plus NLS-HsPex19; (E-H) ALDP-YFP plus NLS-AtPex19_1; (I-L) ALDR-YFP plus NLS-AtPex19_1. Login to comment
154 Approximately 60% of X-ALD ABCD1 mutations are missense mutations, 65% of which result in no detectable ALDP, based on IF (immunofluorescence), indicating that they affect protein Table 1 Quantification of ALDP levels in X-ALD fibroblasts ALDP Mutation IF Immunoblot (% of control) p.Arg74Trp Absent 7.5 + - 0.6 p.Arg104Cys Reduced 35 + - 3.0 p.Ser149Asn Present 77 + - 3.0 p.Asp194His Present 60 + - 13.6 p.Leu220Pro Reduced 21.8 + - 5.4 p.Arg389His Present 40.6 + - 3.6 p.Arg554His Absent 1.0 + - 0.5 p.Ser606Leu Present 25 + - 1.5 p.Glu609Gly Absent 2.1 + - 1.3 p.Glu609Lys Absent 1.8 + - 0.9 p.Ala616Thr Absent 4.3 + - 1.7 p.Leu654Pro Absent 1.5 + - 1.3 p.Arg660Trp Absent 1.6 + - 0.8 p.His667Asp Absent 2.9 + - 1.0 p.Arg113fs Absent - Figure 3 Interaction of mammalian ABCD proteins with Arabidopsis Pex19 in vivo Tobacco plants stably expressing CFP-SKL were co-transfected with 35S::ABCD-YFP fusions andNLS-Pex19constructs.Leafepidermalcellswereimagedusingconfocalmicroscopy:(A-D) ALDP-YFP plus NLS-HsPex19; (E-H) ALDP-YFP plus NLS-AtPex19_1; (I-L) ALDR-YFP plus NLS-AtPex19_1. Login to comment

[hide] A novel mutation in the ABCD1 gene of a Korean boy... Gene. 2012 Apr 25;498(1):131-3. Epub 2012 Feb 1. Park JA, Jun KR, Han SH, Kim GH, Yoo HW, Hur YJ
A novel mutation in the ABCD1 gene of a Korean boy diagnosed with X-linked adrenoleukodystrophy.
Gene. 2012 Apr 25;498(1):131-3. Epub 2012 Feb 1., [PMID:22326269]

Abstract [show]
X-linked adrenoleukodystrophy (ALD; MIM #300100) is a neurodegenerative disorder caused by mutations in the ABCD1 adrenoleukodystrophy protein gene. The ABCD1 gene mutations have been reported by laboratories in China and Japan, but not in Korea. This case report describes a Korean boy diagnosed with X-ALD. Direct sequencing for the ABCD1 gene in this boy and his mother detected Tyr620His missense mutation, caused by cDNA nucleotide change 1858 T>C in exon 8 (c.1858T>C). This missense variant was novel and predicted to be possibly damaging by the PolyPhen and SIFT prediction software. Moreover, this is the first report in Korean.

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67 On the other hand, one Dutch family was identified with the Arg389His (c.1166G>A) missense mutation with normal levels of ALDP. Login to comment
66 On the other hand, one Dutch family was identified with the Arg389His (c.1166G>A) missense mutation with normal levels of ALDP. Login to comment

[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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120 Sixteen of these mutations have been published before (11, 21); the remaining 12 mutations comprise nine missense mutations (A141T, Y281H, R389H, G512S, P543L, R554H, Y559H, R617H, R679R), two frame-shift mutations (del 740, del 2132) and one splice site mutation (ins 8 bp 2252). Login to comment

[hide] Altered expression of ALDP in X-linked adrenoleuko... Am J Hum Genet. 1995 Aug;57(2):292-301. Watkins PA, Gould SJ, Smith MA, Braiterman LT, Wei HM, Kok F, Moser AB, Moser HW, Smith KD
Altered expression of ALDP in X-linked adrenoleukodystrophy.
Am J Hum Genet. 1995 Aug;57(2):292-301., [PMID:7668254]

Abstract [show]
X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disorder with variable phenotypic expression that is characterized by elevated plasma and tissue levels of very long-chain fatty acids. However, the product of the gene defective in ALD (ALDP) is a membrane transporter of the ATP-binding cassette family of proteins and is not related to enzymes known to activate or oxidize fatty acids. We generated an antibody that specifically recognizes the C-terminal 18 amino acids of ALDP and can detect ALDP by indirect immunofluorescence. To better understand the mechanism by which mutations in ALDP lead to disease, we used this antibody to examine the subcellular distribution and relative abundance of ALDP in skin fibroblasts from normal individuals and ALD patients. Punctate immunoreactive material typical of fibroblast peroxisomes was observed in cells from seven normal controls and eight non-ALD patients. Of 35 ALD patients tested, 17 had the childhood-onset cerebral form of the disease, 13 had the milder adult phenotype adrenomyeloneuropathy, 3 had adrenal insufficiency only, and 2 were affected fetuses. More than two-thirds (69%) of all patients studied showed no punctate immunoreactive material. There was no correlation between the immunofluorescence pattern and clinical phenotype. We determined the mutation in the ALD gene in 15 of these patients. Patients with either a deletion or frameshift mutation lacked ALDP immunoreactivity, as expected. Four of 11 patients with missense mutations were also immunonegative, indicating that these mutations affected the stability or localization of ALDP. In the seven immunopositive patients with missense mutations, correlation of the location and nature of the amino acid substitution may provide new insights into the function of this peroxisomal membrane protein. Furthermore, the study of female relatives of immunonegative ALD probands may aid in the assessment of heterozygote status.

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176 In 11 patients, missense mutations that occurred throughout the protein were found: within the transmembrane domains (patients 1, 3, and 4), within the ATP-binding domain (patients 8-12), and on either side of the ATP-binding Table 3 Mutational Analysis of the ALD Gene in IS Unrelated Patients ALDP Patient Phenotype Mutation Consequence Immunoreactivity 1 .................. CALD 825 A-GG K276E + 2.................. AMN 870-2AGAGE291,& 3 .................. CALD 872 G-C E291D 4 .................. AMN 1023 T-IC S342P+ 5 .................. AMN 1166 G-C R389H + 6 .................. CALD 1201 G-AA R401Q + 7 ........ CALD 1415-6 AAG FS@472 8 ........ AMN 1771 G-AA R591Q + 9 ........ Addison 1817 C-T S606L + 10 ................ AMN 1850 G-AA R617H 11 ................ CALD 1876 G-AA A626T 12 ................ Fetus 1884 G-C D629H + 13 ................ CALD 1932 C-UT Q645X 14 ................ AMN 1978 C-OT R660W 15 ........ AMN AExon7-10 Null Mutations in the ALD gene were determined, as described in Methods, in 15 of the ALD patients reported in table 2. Login to comment
178 In 11 patients, missense mutations that occurred throughout the protein were found: within the transmembrane domains (patients 1, 3, and 4), within the ATP-binding domain (patients 8-12), and on either side of the ATP-binding Table 3 Mutational Analysis of the ALD Gene in IS Unrelated Patients ALDP Patient Phenotype Mutation Consequence Immunoreactivity 1 .................. CALD 825 A-GG K276E + 2 .................. AMN 870-2 AGAG E291,& 3 .................. CALD 872 G-C E291D 4 .................. AMN 1023 T-IC S342P + 5 .................. AMN 1166 G-C R389H + 6 .................. CALD 1201 G-AA R401Q + 7 ........ CALD 1415-6 AAG FS@472 8 ........ AMN 1771 G-AA R591Q + 9 ........ Addison 1817 C-T S606L + 10 ................ AMN 1850 G-AA R617H 11 ................ CALD 1876 G-AA A626T 12 ................ Fetus 1884 G-C D629H + 13 ................ CALD 1932 C-UT Q645X 14 ................ AMN 1978 C-OT R660W 15 ........ AMN AExon7-10 Null Mutations in the ALD gene were determined, as described in Methods, in 15 of the ALD patients reported in table 2. Login to comment

[hide] Spectrum of mutations in the gene encoding the adr... Am J Hum Genet. 1995 Jan;56(1):44-50. Ligtenberg MJ, Kemp S, Sarde CO, van Geel BM, Kleijer WJ, Barth PG, Mandel JL, van Oost BA, Bolhuis PA
Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein.
Am J Hum Genet. 1995 Jan;56(1):44-50., [PMID:7825602]

Abstract [show]
X-linked adrenoleukodystrophy (ALD) has been associated with mutations in a gene encoding an ATP-binding transporter, which is located in the peroxisomal membrane. Deficiency of the gene leads to impaired peroxisomal beta-oxidation. Systematic analysis of the open reading frame of the ALD gene, using reverse transcriptase-PCR, followed by direct sequencing, revealed mutations in all 28 unrelated kindreds analyzed. No entire gene deletions or drastic promoter mutations were detected. In only one kindred did the mutation involve multiple exons. The other mutations were small alterations leading to missense (13 of 28) or nonsense mutations, a single amino acid deletion, frameshifts, or splice acceptor-site defects. Mutations affecting a single amino acid were concentrated in the region between the third and fourth putative transmembrane domains and in the ATP-binding domain. Mutations were detected in all investigated ALD kindreds, suggesting that this gene is the only gene responsible for X-linked ALD. This overview of mutations is useful in the determination of structurally and functionally important regions and provides an efficient screening strategy for identification of mutations in the ALD gene.

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85 The mutation T1045C created a novel HpaII site, which was confirmed Table 2 Mutations in the Putative ALD Gene in Patients Studied Genomic- Kindred Type of Mutation and Amino Acid Genomic-PCR Mutation Reference cDNA Alterationa Alterationb Exonc Primers Detectiond Phenotype' Number Missense: C696Tf ................ R104C (R) 1 303F + 821R 303F, 821R AMN 17 G832A ................ S149N (N) 1 702F + 1145R 702F, 931R AMN 8 G841C ................ R152P (K) 1 702F + 1145R 702F, 931R ChALD 27 G874Af ................ R163H (R) 1 702F + 931R 702F, 931R SympCar 14 G966C ................ D194H (D) 1 685F + 1145R 914F, 1145R ChALD 12 T1045C ................ L220P (L) 1 914F + 1145R HpaII AMN 7 G1182A ................. G266R (G) 1 702F + 1231R 914F,1231R AMN 24 G1552A ................. R389H (R) 3 1479F + 1861R 1479F,1752R AMN 20 (2X): G2211A................. E609K(E) 8 544F*+ 1078R*h 544F*, 876R* AMN 13,18 A2212G ................ E609G (E) 8 544F*+ 1078R*h 544F*, 876R* ChALD 5 C2235Tf................ R617C (R) 8 544F* + 2742R 544F*, 876R* ChALD 23 C2364Tf................ R660W (R) 9 544F* + 2742R 2312F, 1078R* AMN 21 Amino acid deletion: del 2355-2357 ........... del 1657(V) 9 849F* + 2478Rh 2312F,1078R* ChALD 6 Nonsense: C783Tf ................ Q133h 1 702F + 931R 702F, 931R ChALD 26 G797A ................ W137h 1 685F +1145R 702F,931R ChALD 10 C855T ................ Q157h 1 702F + 1145R 702F,931R AMN 9 C929A ................ Y181h 1 702F + 1145R HpaIl ChALD 15 Frameshift: delC442 ................ A19> 1 303F + 821R 303F,593R ChALD 2 del C663 ................ G92> 1 303F + 840R 576F, 821R ChALD 22 dell71-1178 ........... F261> 1 702F + 1231R 914F,1231R ChALD 28 (4X): del 1801-1802 ........... E471> 5 1781F + 1861R Polyacrylamide gel ChALD, AMN 3,4,16,25 alt 1989-2377 ........... P534> 6-9 1890F +2669R 1890F,1078R* AMN 11 Splice defect: de12021-2054 ........... R545> SA 7 1880F +2132R 1880F,2114R ChALD 1 ins 8 bp 2251f ............ R622> SA 9 849F* + 1078R*h 849F*, 1078R* AMN 19 a Nucleotide numbers refer to Mosser et al. (1993), EMBL database Z21876. 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
187 Patient 7 has a G + A transition at nucleotide 1166 causing a missense mutation, R389H. Login to comment

[hide] X-linked adrenomyeloneuropathy due to a novel miss... J Peripher Nerv Syst. 2011 Dec;16(4):353-5. doi: 10.1111/j.1529-8027.2011.00367.x. Engelen M, van der Kooi AJ, Kemp S, Wanders RJ, Sistermans EA, Waterham HR, Koelman JT, van Geel BM, de Visser M
X-linked adrenomyeloneuropathy due to a novel missense mutation in the ABCD1 start codon presenting as demyelinating neuropathy.
J Peripher Nerv Syst. 2011 Dec;16(4):353-5. doi: 10.1111/j.1529-8027.2011.00367.x., [PMID:22176151]

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46 Recently a patient with pes cavus, spasticity and a primarily demyelinating neuropathy with variable, focal slowing of motor nerve conduction velocities (NCVs) but relative preservation of motor and sensory amplitudes was described who was found to have both a PMP22 gene deletion consistent with a hereditary neuropathy with liability to pressure palsies and a c.1166G>A mutation in the ABCD1 gene, causing an amino acid substitution at codon 389 (p.Arg389His) (Hodapp et al., 2006). Login to comment

[hide] Double trouble in hereditary neuropathy: concomita... Arch Neurol. 2006 Jan;63(1):112-7. Hodapp JA, Carter GT, Lipe HP, Michelson SJ, Kraft GH, Bird TD
Double trouble in hereditary neuropathy: concomitant mutations in the PMP-22 gene and another gene produce novel phenotypes.
Arch Neurol. 2006 Jan;63(1):112-7., [PMID:16401743]

Abstract [show]
BACKGROUND: Mutations in the peripheral myelin protein 22 (PMP-22) gene are the most common cause of Charcot-Marie-Tooth neuropathy and may rarely occur in combination with other neurogenetic diseases. OBJECTIVE: To characterize 3 families having a mutation in PMP-22 in addition to another neurogenetic disease mutation. DESIGN: Clinical, electrophysiologic, and genetic evaluations were made of 3 families with more than 1 genetic neuromuscular disease. SETTING AND PATIENTS: Family members were evaluated in neurogenetic and muscular dystrophy clinics in a university medical center setting. RESULTS: Three unusual families were found: (1) 2 young brothers each having a PMP-22 duplication and a missense mutation in the GJB1 (Connexin-32) gene; (2) a 32-year-old woman having a PMP-22 duplication and a 1000-fold CTG repeat expansion in the DMPK gene (DM1 myotonic dystrophy); and (3) a 39-year-old man with a PMP-22 deletion and a missense mutation in the ABCD1 gene (adrenomyeloneuropathy). The mutations were "additive," causing a more severe phenotype than expected with each individual disease and coinciding with the important impact of each gene on peripheral nerve function. CONCLUSIONS: Individuals having 2 separate mutations in neuromuscular disease-related genes may develop unusually severe phenotypes. Neurologists should be alert to this possibility.

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81 DNA sequencing revealed a G-to-A substitution at nucleotide 1552 in the ABCD1 gene, causing an amino acid substitution at codon 389 (R389H) (genetic analysis by Kennedy Krieger Institute, Baltimore, Md). Login to comment

[hide] X-linked adrenoleukodystrophy: clinical, metabolic... Biochim Biophys Acta. 2012 Sep;1822(9):1465-74. doi: 10.1016/j.bbadis.2012.03.012. Epub 2012 Mar 28. Kemp S, Berger J, Aubourg P
X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects.
Biochim Biophys Acta. 2012 Sep;1822(9):1465-74. doi: 10.1016/j.bbadis.2012.03.012. Epub 2012 Mar 28., [PMID:22483867]

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X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease. The two main clinical phenotypes of X-ALD are adrenomyeloneuropathy (AMN) and inflammatory cerebral ALD that manifests either in children or more rarely in adults. About 65% of heterozygote females develop symptoms by the age of 60years. Mutations in the ABCD1 gene affect the function of the encoded protein ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane protein. ALDP deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues. While all patients have mutations in the ABCD1 gene, there is no general genotype-phenotype correlation. Environmental factors and a multitude of modifying genes appear to determine the clinical manifestation in this monogenetic but multifactorial disease. This review focuses on the clinical, biochemical, genetic and pathophysiological aspects of X-ALD.

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247 The affected members of this kindred carry a missense mutation p.Arg389His that results in stable ALDP correctly localized to peroxisomes. Login to comment

[hide] X-linked adrenoleukodystrophy in women: a cross-se... Brain. 2014 Mar;137(Pt 3):693-706. doi: 10.1093/brain/awt361. Epub 2014 Jan 29. Engelen M, Barbier M, Dijkstra IM, Schur R, de Bie RM, Verhamme C, Dijkgraaf MG, Aubourg PA, Wanders RJ, van Geel BM, de Visser M, Poll-The BT, Kemp S
X-linked adrenoleukodystrophy in women: a cross-sectional cohort study.
Brain. 2014 Mar;137(Pt 3):693-706. doi: 10.1093/brain/awt361. Epub 2014 Jan 29., [PMID:24480483]

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X-linked adrenoleukodystrophy is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal transporter of very long-chain fatty acids. A defect in the ABCD1 protein results in elevated levels of very long-chain fatty acids in plasma and tissues. The clinical spectrum in males with X-linked adrenoleukodystrophy has been well described and ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. As in many X-linked diseases, it was assumed that female carriers remain asymptomatic and only a few studies addressed the phenotype of X-linked adrenoleukodystrophy carriers. These studies, however, provided no information on the prevalence of neurological symptoms in the entire population of X-linked adrenoleukodystrophy carriers, since data were acquired in small groups and may be biased towards women with symptoms. Our primary goal was to investigate the symptoms and their frequency in X-linked adrenoleukodystrophy carriers. The secondary goal was to determine if the X-inactivation pattern of the ABCD1 gene was associated with symptomatic status. We included 46 X-linked adrenoleukodystrophy carriers in a prospective cross-sectional cohort study. Our data show that X-linked adrenoleukodystrophy carriers develop signs and symptoms of myelopathy (29/46, 63%) and/or peripheral neuropathy (26/46, 57%). Especially striking was the occurrence of faecal incontinence (13/46, 28%). The frequency of symptomatic women increased sharply with age (from 18% in women <40 years to 88% in women >60 years of age). Virtually all (44/45, 98%) X-linked adrenoleukodystrophy carriers had increased very long-chain fatty acids in plasma and/or fibroblasts, and/or decreased very long-chain fatty acids beta-oxidation in fibroblasts. We did not find an association between the X-inactivation pattern and symptomatic status. We conclude that X-linked adrenoleukodystrophy carriers develop an adrenomyeloneuropathy-like phenotype and there is a strong association between symptomatic status and age. X-linked adrenoleukodystrophy should be considered in the differential diagnosis in women with chronic myelopathy and/or peripheral neuropathy (especially with early faecal incontinence). ABCD1 mutation analysis deserves a place in diagnostic protocols for chronic non-compressive myelopathy.

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141 Table 1 Summary of symptoms and signs of all the female participating in the study Family Age (years) Urinary incontinence Faecal incontinence Gait disorder Sensory complaints Sensory disturbance Spasticity Weakness Pathological reflexes EDSS Mutation ABCD1 protein A 44 No No Yes No No No No Yes 1.0 p.Pro480Thr Absent A 56 Yes Yes No No No No No Yes 1.5 p.Pro480Thr Absent AA 45 No No No No No No No No 0 p.Arg660Trp Absent AA 59 Yes No Yes No No No Yes Yes 3.5 p.Arg660Trp Absent AA 75 Yes No Yes No Yes Yes Yes Yes 6.0 p.Arg660Trp Absent B 42 Yes Yes Yes No Yes Yes Yes Yes 4.0 p.Leu220Pro Reduced B 44 No No No No No No No No 0 p.Leu220Pro Reduced B 44 No No No No No No No No 0 p.Leu220Pro Reduced B 51 No No No Yes Yes No No No 1.0 p.Leu220Pro Reduced B 59 No No No Yes Yes No Yes No 2.0 p.Leu220Pro Reduced C 44 No No No No No No No No 0 p.Gln133* Absent D 38 Yes Yes Yes No Yes Yes Yes Yes 6.0 p.Leu654Pro Absent D 57 Yes No Yes Yes Yes No No Yes 5.5 p.Leu654Pro Absent E 31 No No No No No No No No 0 p.Arg74Trp Absent E 37 No No No No No No No No 0 p.Arg74Trp Absent E 60 No No Yes No Yes Yes Yes Yes 5.5 p.Arg74Trp Absent F 35 No No No No No No No No 0 p.Met1Val Absent G 42 No Yes No No No No No No 1.0 p.Ala245Asp Present H 61 Yes Yes Yes Yes Yes No No Yes 3.5 exon8-10del Absent I 71 No No No No Yes No No Yes 2.0 p.Glu609Lys Absent J 42 No No No No Yes No No Yes 1.5 p.Glu90* Absent K 31 No No No No No No No No 0 p.Pro543Leu Absent K 48 Yes No No No Yes No No Yes 2.5 p.Pro543Leu Absent K 57 No No Yes Yes Yes No Yes Yes 3.5 p.Pro543Leu Absent K 60 Yes No No No Yes No No Yes 3.5 p.Pro543Leu Absent L 51 Yes No Yes No Yes Yes Yes Yes 6.5 p.Ile657del Absent M 22 No No No No No No No No 0 p.Ser149Asn Reduced M 40 No No No No No No No No 0 p.Ser149Asn Reduced N 29 No No No No No No No No 0 p.Arg389His Reduced N 45 Yes No No Yes No No No No 2.0 p.Arg389His Reduced N 57 Yes Yes Yes Yes Yes No No No 3.5 p.Arg389His Reduced N 70 No No Yes No Yes No Yes Yes 3.5 p.Arg389His Reduced O 40 Yes Yes Yes Yes Yes No No Yes 3.5 p.Glu609Lys Absent P 59 Yes Yes Yes Yes Yes Yes Yes Yes 6.0 p.Leu215* Absent Q 39 No Yes Yes No Yes No No No 3.0 p.Val208Trpfs Absent R 28 No No No No No No No No 0 p.Pro480Thr Absent S 35 No No No No No No No No 0 p.His283Tyr Reduced (continued) Correlation studies of X-inactivation with asymptomatic or symptomatic status The distribution of ABCD1 allele-specific expression (which will be referred to as the pattern of X-inactivation) is shown in Fig. 5A. Login to comment

[hide] Clinical and genetic aspects in twelve Korean pati... Yonsei Med J. 2014 May;55(3):676-82. doi: 10.3349/ymj.2014.55.3.676. Epub 2014 Apr 1. Park HJ, Shin HY, Kang HC, Choi BO, Suh BC, Kim HJ, Choi YC, Lee PH, Kim SM
Clinical and genetic aspects in twelve Korean patients with adrenomyeloneuropathy.
Yonsei Med J. 2014 May;55(3):676-82. doi: 10.3349/ymj.2014.55.3.676. Epub 2014 Apr 1., [PMID:24719134]

Abstract [show]
PURPOSE: This study was designed to investigate the characteristics of Korean adrenomyeloneuropathy (AMN) patients. MATERIALS AND METHODS: We retrospectively selected 12 Korean AMN patients diagnosed by clinical analysis and increased plasma content of very long chain fatty acids. RESULTS: All 12 patients were men. Patient ages at symptom onset ranged from 18 to 55 years. Family history was positive in two patients. The phenotype distributions consisted of AMN without cerebral involvement in seven patients, AMN with cerebral involvement in two patients, and the spinocerebellar phenotype in three patients. Nerve conduction studies revealed abnormalities in four patients and visual evoked tests revealed abnormalities in three patients. Somatosensory evoked potential tests revealed central conduction defects in all of the tested patients. Spinal MRI showed diffuse cord atrophy or subtle signal changes in all 12 patients. Brain MRI findings were abnormal in six of the nine tested patients. These brain abnormalities reflected the clinical phenotypes. Mutational analysis identified nine different ABCD1 mutations in 10 of 11 tested patients. Among them, nine have been previously reported and shown to be associated with various phenotypes; one was a novel mutation. CONCLUSION: In conclusion, the present study is the first to report on the clinical and mutational spectrum of Korean AMN patients, and confirms various clinical presentations and the usefulness of brain MRI scan.

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89 The Mutational Analysis of Korean Patients with Adrenomyeloneuropathy Exon Mutation Allele Type Reference Adrenomyeloneuropathy without cerebral involvement 1 1 c.479T>C p.Leu160Pro Missense Sutovsk&#fd;, et al.13 2 3 c.1166G>A p.Arg389His Missense Kok, et al.14 3 9 c.1970_72del p.Ile657del In-frame deletion Ligtenberg, et al.15 4 1 c.421G>A p.Ala141Thr Missense Kok, et al.14 5 Not found 6 7 c.1679C>T p.Pro560Leu Missense Kemp, et al.6 7 Not available Adrenomyeloneuropathy with cerebral involvement 8 7 c.1679C>T p.Pro560Leu Missense Kemp, et al.6 9 1 c.225_242del p.Trp77_Leu82del Deletion Lee, et al.9 Spinocerebellar phenotype 10 1 c.277_296dup20 p.Leu93fs Frameshift Novel 11 7 c.1661G>A p.Arg554His Missense Kemp, et al.6 12 IVS1 c.901-1G>A p.Val301fs Frameshift Kemp, et al.6 IVS, intervening sequence. Login to comment