Disease relevance of ABCD1

• X-linked adrenoleukodystrophy (X-ALD) results from mutations in ABCD1 [1].
• X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disease caused by loss of function of the peroxisomal transporter ABCD1 (ALD), which results in accumulation of very long chain fatty acids (VLCFAs) in organs and serum, central demyelination and peripheral axonopathy and Addison's disease [2].
• The neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD) is caused by ABCD1 mutations and characterized by very long-chain fatty acid (VLCFA) accumulation [3].
• Adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder, is a severe neurodegenerative disease associated with an impairment of very long chain fatty acids beta-oxidation [4].
• CASE REPORT: We report a novel missense mutation in the ABCD1 gene in a 47-year-old French-Canadian female with spastic paraparesis and no confirmed family history of X-linked adrenoleukodystrophy [5].

Psychiatry related information on ABCD1

• It constitutes the best marker on the X chromosome and should be of great use for the genetic study of three important diseases: hemophilia A, mental retardation with a fragile X chromosome, and adrenoleukodystrophy [6].
• Secondary endpoints included body image evaluation (determined by ABCD questionnaire), facial aesthetic satisfaction (determined by Visual Analogue Scale), and aesthetic pre- and post-picture comparisons by independent reviewers [7].
• Presenile-onset cerebral adrenoleukodystrophy presenting as Balint's syndrome and dementia [8].
• We have investigated the immunohistochemical localization of Fas antigen in postmortem brain tissue from control subjects, patients with Alzheimer-type dementia (ATD), and from a few patients with diffuse Lewy body disease, progressive supranuclear palsy and adrenoleukodystrophy [9].
• The staining intensity of CD44 in liver specimens obtained from patients with ALD who were active in alcohol consumption were significantly higher when compared with patients with ALD after abstinence [10].

High impact information on ABCD1

• Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease [11].
• Additional follow-up from the ABCD trial in patients with type 2 diabetes and hypertension [12].
• Lovastatin for X-linked adrenoleukodystrophy [13].
• In the current study, we analyzed data on a secondary end point (the incidence of myocardial infarction) in the subgroup of patients in the ABCD Trial who had hypertension [14].
• Lorenzo's oil and thrombocytopenia in patients with adrenoleukodystrophy [15].

Chemical compound and disease context of ABCD1

• Impaired metabolism of retinol has been shown to occur in alcohol-induced liver disease (ALD) [16].
• These results suggest that elevated levels of AGEs in tissues and serum of diabetic patients may inhibit endogenous antibacterial proteins by binding to this conserved AGE-binding cysteine-bounded domain 'ABCD' motif, thereby increasing susceptibility to bacterial infections in the diabetic population [17].
• Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy [18].
• Peroxisomal lignoceroyl-CoA ligase deficiency in childhood adrenoleukodystrophy and adrenomyeloneuropathy [19].
• Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by demyelination, adrenal insufficiency, and accumulation of saturated very-long-chain fatty acids (VLFA), particularly hexacosanoate (C26:0) [20].

Biological context of ABCD1

• These children have the earliest onset (age 7.2 +/- 1.7 years) among the clinical phenotypes for ABCD1 mutations, but onset does not occur at <3 years of age [1].
• Mutations in DXS1357E and the ABCD1 promoter region have not been described previously [1].
• Pxa1p, a putative ortholog of ALDP, is involved in peroxisomal beta-oxidation of fatty acids while YKL741 is an open reading frame found by the yeast genome sequencing project [21].
• ALDP and PMP70 share sequence homology and both are implicated in genetic diseases [21].
• 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 [22].

Anatomical context of ABCD1

• We show that in cultured cells, cholesterol-loading induces ABCD1 [3].
• By using transient and stable overexpression of human cDNAs encoding ALDP and its closest relative ALDRP, we could restore the impaired peroxisomal beta-oxidation in fibroblasts of X-ALD patients [23].
• Three half ATP-binding cassette transporters (ALDP, ALDR, PMP70) are known to be present in the human peroxisome membrane [24].
• Defects in the ALD gene are the primary cause of adrenoleukodystrophy, a demyelinating disorder of the central nervous system [25].
• X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder associated with elevated levels of saturated unbranched very-long-chain fatty acids (VLCFA; C > 22:0) in plasma and tissues, and reduced VLCFA beta-oxidation in fibroblasts, white blood cells, and amniocytes from X-ALD patients [26].

Associations of ABCD1 with chemical compounds

• Bidirectional sequencing of the entire coding ALD gene disclosed a cytosine to guanine transversion at nucleotide 1451 in exon five, resulting in substitution of proline 484 by arginine [27].
• No differences were noted in daily retinol intake, but subjects with ALD had significantly lower concentrations of retinol in plasma (ALD1: 1.81+/-0.17 micromol/l [mean+/-S.E.M.]; ALD2: 1.95+/-0.24 micromol/l; ALD3: 0.67+/-0.13 micromol/l) compared to controls (2.76+/-0.19 micromol/l) [16].
• To understand the cell biology and function of mammalian peroxisomal ABC transporters and to determine their role in the pathogenesis of X-ALD we developed a system for expressing functional ABC protein domains in fusion with the maltose binding protein [28].
• The presence of increased concentrations of serum pipecolic acid and the bile acid intermediate, trihydroxycoprostanic acid, in the neonatal ALD patient are associated with a generalized diminution of peroxisomal activities that was not observed in the patient with X-linked ALD [29].
• Adrenoleukodystrophy (ALD) is an inherited disorder of fatty acid metabolism marked by accumulation of very long chain saturated fatty acids (VLCFA), especially the 26-carbon acid, hexacosanoic acid (HA), in membranes and tissues [30].

Physical interactions of ABCD1

• Farnesylated wild-type PEX19p and a farnesylation-deficient mutant PEX19p did not differ in their ability to bind to ALDP [31].

Other interactions of ABCD1

• Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy [32].
• The ALDR gene is a candidate for a modifier gene, accounting for the strikingly varying clinical courses of ALD observed even within a family [25].
• The ALD gene has been positioned on a pulsed-field map between DXS15 and the L1CAM gene, about 650 kb upstream from the color pigment genes [4].
• The PEX19p interaction occurs in an internal N-terminal region of ALDP which we verified to be important for proper peroxisomal targeting of this protein [31].
• Human adrenoleukodystrophy protein and related peroxisomal ABC transporters interact with the peroxisomal assembly protein PEX19p [31].

Analytical, diagnostic and therapeutic context of ABCD1

• Immunofluorescence analysis demonstrated that the functional replacement of ALDP by ALDRP was not due to stabilization of the mutated ALDP itself [23].
• Western blot analysis showed the absence of ALDP in the brain, spinal cord, lung, and kidney and normal expression of PMP70 in the liver, lung, and kidney [33].
• Immunoelectron microscopy and subcellular fractionation revealed that the overexpressed ALDP was distributed in various subcellular organelles including mitochondria, nucleus and peroxisomes [34].
• The complete coding region of the ABCD1 gene was amplified by reverse transcription polymerase chain reaction (RT-PCR) or genomic PCR [35].
• The levels of the ABCD1 transcript in one patient (corresponding to a nonsense mutation) were below the detection limit of Northern-blotting analysis [35].

References