| Full gene name: | ATP-binding cassette, sub-family D (ALD), member 1 |
|---|---|
| Entrez Gene ID: | 215 |
| Location: | Xq28 |
| Synonyms: | ALD, ALDP, ABC42, AMN |
| Type: | protein-coding |
SNPs given by the user that are near or inside this gene:
| SNP | Distance (bp) | Direction |
|---|---|---|
| rs3020789 | 97336 | upstream |
The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ALD subfamily, which is involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs in the organelle. All known peroxisomal ABC transporters are half transporters which require a partner half transporter molecule to form a functional homodimeric or heterodimeric transporter. This peroxisomal membrane protein is likely involved in the peroxisomal transport or catabolism of very long chain fatty acids. Defects in this gene have been identified as the underlying cause of adrenoleukodystrophy, an X-chromosome recessively inherited demyelinating disorder of the nervous system. [provided by RefSeq, Jul 2008]
| OMIM ID: | `OMIM ID 300371 `_ |
|---|
Allelic Variants (Selected Examples)
.0001 ADRENOLEUKODYSTROPHY
In fibroblasts from a patient with adrenoleukodystrophy (300100), Cartier et al. (1993) found a 4.2-kb transcript, as in normal fibroblasts, by Northern blot analysis. However, a probe from the 5-prime end of the ALD gene detected an abnormal 1.9-kb TaqI restriction DNA fragment pointing to a novel TaqI restriction site in exon 1. Further study revealed a G-to-A transition at base 1258 in the ALD allele of the affected patient and in one allele of his mother, converting glutamic acid to lysine at residue 291.
.0002 ADRENOLEUKODYSTROPHY
Berger et al. (1994) used PCR to amplify fragments of ALD cDNA from a patient with adolescent ALD (300100). Bidirectional sequencing of the entire coding ALD gene disclosed a C-to-G transversion at nucleotide 1451 in exon 5, resulting in substitution of proline-484 by arginine. Altogether, 5 of 9 sibs had the mutation: the proband with adolescent ALD, 2 with cerebral ALD, 1 with adrenomyeloneuropathy, and 1 with Addison disease only. All 5, as well as the symptomatic mother, showed accumulation of very long chain fatty acids. The mutation was not found in unaffected members of the family in 5 unrelated ALD patients or in 20 controls. The mother had slowly progressive spastic paraparesis. Thus, 5 different phenotypes were observed in the 6 affected members of the family.
.0003 ADRENOLEUKODYSTROPHY
In a patient with ALD (300100), Kemp et al. (1995) found an A-to-G transition at position -2 of the splice acceptor site at the 3-prime end of intron 6. In the patient’s mother, both the normal and the mutant allele were present. Exon 7 of the ALD gene contains a sequence that can serve as a cryptic splice site. Splicing at this site creates an mRNA of which 34 bp are deleted, which leads to a frameshift at amino acid arg545, immediately followed by a stop codon.
.0004 ADRENOLEUKODYSTROPHY
In a patient with ALD (300100), Kemp et al. (1995) found an insertion of 8 bp at the start of exon 9 of the ALD gene. Sequencing of the genomic fragment containing the 149-bp intron 8 revealed that the G at position -10 of the 3-prime splice acceptor site of exon 9 was substituted with an A. This mutation created an upstream novel splice acceptor site. The 8-bp insertion led to a frameshift at position arg622 and a premature stop codon 16 amino acids downstream.
.0005 ADRENOMYELONEUROPATHY
In a family in which 1 male had adrenomyeloneuropathy (300100), Krasemann et al. (1996) identified a de novo mutation in exon 3 of the ALD gene: a C-to-G transversion at nucleotide 1551 resulting in an arg389-to-gly substitution.
.0006 ADRENOLEUKODYSTROPHY
Fuchs et al. (1994) studied 10 unrelated German patients with adrenoleukodystrophy (300100) and identified an A-to-G transition at nucleotide 829 in exon 1 of the ALD gene, converting asparagine-148 to serine.
.0007 ADRENOLEUKODYSTROPHY
Fuchs et al. (1994) studied 10 unrelated German patients with adrenoleukodystrophy (300100) and identified a T-to-G transition at nucleotide 906 in exon 1 of the ALD gene, converting tyrosine-174 to aspartic acid. The mutation creates a new TaqI restriction site.
.0008 ADRENOLEUKODYSTROPHY
Fuchs et al. (1994) studied 10 unrelated German patients with adrenoleukodystrophy (300100) and identified a G-to-A transition at nucleotide 1182 in exon 1 of the ALD gene, converting glycine-266 to arginine.
.0009 ADRENOLEUKODYSTROPHY
Fuchs et al. (1994) studied 10 unrelated German patients with adrenoleukodystrophy (300100) and identified a G-to-A transition at nucleotide 1588 in exon 3 of the ALD gene, converting arginine-401 to glutamine.
.0010 ADRENOLEUKODYSTROPHY
Fuchs et al. (1994) studied 10 unrelated German patients with adrenoleukodystrophy (300100) and identified a C-to-T transition at nucleotide 1638 in exon 4 of the ALD gene, converting arginine-418 to tryptophan. The patient’s mother carried the same nucleotide substitution in heterozygous form.
.0011 ADRENOMYELONEUROPATHY
In 1 patient with Addison disease at age 10 years and adrenomyeloneuropathy (300100) at age 15 years, Fanen et al. (1994) identified a C-to-T transition at nucleotide 1776 in exon 4 of the ALD gene, converting arginine to a premature termination codon at residue 464. The mutation creates a new BglII restriction site.
.0012 ADRENOLEUKODYSTROPHY
In 3 unrelated patients with the classic childhood form of adrenoleukodystrophy (300100), Barcelo et al. (1994) and Fuchs et al. (1994) identified a 2-bp (AG) deletion at nucleotides 1801-1802 in exon 5, leading to a frameshift after the first 471 amino acids and a premature termination codon. The predicted mutated protein would have 553 amino acids (192 residues less than the normal protein), losing both ATP binding sites.
.0013 ADRENOLEUKODYSTROPHY
Fuchs et al. (1994) studied 10 unrelated German patients with adrenoleukodystrophy (300100) and identified a G-to-T transition at nucleotide 1815 in exon 5 of the ALD gene, converting glutamic acid to a premature termination codon at residue 477.
.0014 ADRENOLEUKODYSTROPHY
Fuchs et al. (1994) studied 10 unrelated German patients with adrenoleukodystrophy (300100) and identified a C-to-T transition at nucleotide 1930 in exon 6 of the ALD gene, converting serine-515 to phenylalanine.
.0015 ADRENOLEUKODYSTROPHY
Fanen et al. (1994) identified a 1-bp deletion at nucleotide 1937 of the ALD gene, leading to a termination codon at position 557 in exon 6 and a truncated protein. The mutation was detected in the heterozygous mother of a boy who died at age 13 years from cerebral adrenoleukodystrophy (300100).
.0016 ADRENOMYELONEUROPATHY
In an adult patient who developed adrenomyeloneuropathy (300100) at age 27 years, Fanen et al. (1994) identified a C-to-T transition at nucleotide 1938 in exon 6 of the ALD gene, converting arginine-518 to tryptophan.
.0017 ADRENOMYELONEUROPATHY
Fanen et al. (1994) identified a G-to-A substitution at position 2020, which is the first nucleotide of the donor splice site of intron 6 of the ALD gene. The mutation was detected in an adult who developed adrenomyeloneuropathy (300100) at age 28 years and died at age 43 years from cerebral involvement. This family illustrates the marked clinical variation of adrenoleukodystrophy: 2 infantile cerebral cases, 1 pure adrenomyeloneuropathy case, and 1 Addison disease case were diagnosed among the brothers or nephews of this patient.
.0018 ADRENOLEUKODYSTROPHY
In a family in which 2 brothers had cerebral adrenoleukodystrophy (300100), one at age 7 years and the other at age 9 years, Fanen et al. (1994) identified a 2-bp (TA) deletion at nucleotide 2177 of the ALD gene, leading to a termination codon at position 599 in exon 8 and a truncated protein.
.0019 ADDISON DISEASE
In a patient who had Addison disease without neurologic involvement at 20 years of age, Fanen et al. (1994) identified a C-to-T transition at nucleotide 2203 in exon 8 of the ALD gene, converting serine-606 to leucine.
.0020 ADDISON DISEASE
In a family in which the affected propositus had isolated Addison disease at age 21 years, Fanen et al. (1994) identified a 1-bp (G) deletion at nucleotide 2204 of the ALD gene, leading to a termination codon at position 635 in exon 8 and a truncated protein.
.0021 ADRENOMYELONEUROPATHY
In a patient who developed adrenomyeloneuropathy (300100) with cerebral involvement at age 33 years, Fanen et al. (1994) identified a G-to-A transition at nucleotide 2236 in exon 8 of the ALD gene, converting arginine-617 to histidine. The mutation leads to a conservative change at the first amino acid of the Walker B motif. The mutation was absent in DNA from the patient’s mother, who had normal plasma VLCFA levels (predicting a noncarrier status). Therefore, the arg617-to-his mutation presented by this patient is likely to be a de novo mutation.
.0022 ADRENOLEUKODYSTROPHY
Fanen et al. (1994) identified a C-to-T transition at nucleotide 2235 in exon 8 of the ALD gene, converting arginine-617 to cysteine. The mutation was discovered in a family in which the index case died of cerebral adrenoleukodystrophy (300100) at age 9 years. DNA from this patient was not available for study, but the mutation was shown to be present in his heterozygous mother and sister and absent in his normal brother, sister, and aunt.
.0023 ADRENOLEUKODYSTROPHY
The glu291-to-lys mutation of the ALD gene (300371.0001) is a recognized cause of adrenoleukodystrophy (300100). Kano et al. (1998) described deletion of codon 291 (GAG) in a Japanese family with a variety of phenotypes in affected individuals. Whereas the proband was classified as having a rare intermediate type of adult cerebral and cerebello-brainstem form of ALD, his younger brother and nephew had the childhood type of ALD. Another nephew was classified as having an adolescent form. At 47 years of age, the proband developed depression, personality change, forgetfulness, and carelessness. He was noted to be severely amotivational, apathetic, and irritable. These behavioral abnormalities resulted in occupational and social compromise and hospitalization at age 48. No skin pigmentation was noted. The level of tau (157140) in the proband’s cerebrospinal fluid was as high as that of patients with Alzheimer disease (104300). His brain magnetic resonance image showed bilateral abnormalities in the cerebellar hemispheres and brainstem, but not in the cerebral white matter, where marked reductions of cerebral blood flow and oxygen metabolism were clearly demonstrated by positron emission tomography. The proband’s younger brother developed mental deterioration, inactiveness, impaired vision, slurring of speech, and gait disturbance at age 8. He died 1 year later of respiratory failure. Autopsy was performed in his case and in that of one of the nephews, who had onset of symptoms at age 7 and died at age 9. Autopsy in both showed massive demyelination of the cerebral white matter but sparing of the U-fibers, compatible with childhood ALD.
.0024 ADRENOLEUKODYSTROPHY
Guimaraes et al. (2001) found a splice site mutation in the ABCD1 gene which was associated with production of a small quantity of correctly spliced mRNA molecules and a small amount of ALD protein detected by Western blot analysis. The atypical and relatively mild early course of the patient was attributed to the existence of some normal ALDP. The patient was a 23-year-old man who had developed normally until the age of 9 years, when he was diagnosed with Addison disease. At that time, no neurologic involvement could be observed. Five years later, he was biochemically diagnosed as ALD (300100); VLCFA levels were found to be increased in both plasma and skin fibroblasts. At the age of 21 years, muscular weakness and difficulty in walking led him to a new clinical evaluation; spastic paraparesis with neurophysiologic abnormalities with an altered spinal cord MRI and a normal cerebral MRI were found. Eighteen months later, the patient displayed a cerebral AMN subphenotype associated with an affected cerebellum. He was in a vegetative state at the time of report.
.0025 ADRENOLEUKODYSTROPHY
Guimaraes et al. (2001) described a ‘leaky’ splicing mutation in a patient with atypical ALD (300100). The alteration was at the -1 position of the donor splice site of exon 1. The mutation resulted in the utilization of a cryptic 5-prime splice site within intron 1. Nevertheless, this change allowed for some correct splicing. Western blot analysis showed the existence of normal-migrating ALD protein. However, as expected, the levels of this protein were greatly decreased. The patient was a 44-year-old man who showed an AMN pure subphenotype of X-ALD. He was diagnosed with Addison disease at the age of 22 years. Ten years later spastic paraparesis was manifested and the biochemical diagnosis (increased VLCFA levels in plasma and fibroblasts) established him as an X-ALD patient.
.0026 ADRENOMYELONEUROPATHY
In a large kindred in which 22 members over 6 generations had adrenomyeloneuropathy (300100), O’Neill et al. (2001) identified a 26-bp deletion (nucleotides 369-394) in the N terminus of the ABCD1 gene, resulting in deletion of amino acids 1-65, including the translation initiation codon. In cells of affected members, the protein was found at reduced levels and appeared to localize normally within the cell, but beta-oxidative function was severely reduced to approximately 20% of normal. The kindred had a highly concordant phenotype with onset in the thirties or forties of a progressive gait disturbance, lower extremity spasticity, hyperreflexia, and occasional sensory abnormalities. The mutation segregated with the disease in 5 affected men and 7 affected women who were tested and was absent in 30 unaffected family members and 40 normal controls, suggesting X-linked dominant inheritance with 100% disease penetrance in female carriers.
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