GeneBe

ABCD1

protein-coding

ATP binding cassette subfamily D member 1, the group of ATP binding cassette subfamily D

Gene summary

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]

Previous symbols:
  • ALD

MANE transcript

NM_000033.4

Inheritance

XL, XLR, AD

ClinVar variants

P:585U:451B:493

Top phenotype

Adrenoleukodystrophy

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:153,724,856-153,744,755

External References & Databases

Ensembl (ENSG00000101986)NCBI Gene (215)OMIM (300371)HGNC:61GenCCUniProt (P33897)AlphaFoldClinVar (ABCD1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~19.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

adrenoleukodystrophySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0018544

Submitter: PanelApp Australia

adrenoleukodystrophyDEFINITIVE

Inheritance Pattern: XLR

Disease ID:MONDO:0018544

Submitter: Natera

adrenoleukodystrophyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0018544

Submitter: G2P

Hirschsprung diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018309

Submitter: Orphanet

hereditary spastic paraplegiaSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0019064

Submitter: Genomics England PanelApp

X-linked cerebral adrenoleukodystrophyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010247

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

X-linked cerebral adrenoleukodystrophySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010247

Submitter: Orphanet

adrenomyeloneuropathySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0015339

Submitter: Orphanet

adrenoleukodystrophyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0018544

Submitter: ClinGen

The relationship between *ABCD1* and adrenoleukodystrophy (ABCD1 deficiency), including X-linked cerebral adrenoleukodystrophy and adrenomyeloneuropathy (AMN), and isolated adrenal insufficiency, inherited in the X-linked pattern, has been evaluated using the ClinGen Clinical Validity Framework as of November, 2020. This association was made using case-level and experimental data. The *ABCD1* gene encodes an ATP-binding cassette half-transporter (ALDP) located in peroxisomes. Using positional cloning, Moser et al. (1993) discovered that this gene was partially deleted in 6 of 85 unrelated patients with adrenoleukodystrophy (ALD), who exhibit neurological symptoms as well as the pathognomonic feature of very long chain fatty acid (VLCFA) accumulation. Since then, several hundreds of inherited and de novo variants (including missense, nonsense, splice site, delins and structural arrangements) have been associated with ABCD1 deficiency, many of which have decreased or absent protein expression and localization at the peroxisomes (PMIDs: 7825602, 8651290, 11748843, 15811009, 21700483). Summary of Case Level Data (12 points): The association is seen in at least 33 probands in 4 publications (PMID: 15811009, 8651290, 7825602, 21700483). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is expected to be hemizygous loss of function. Female carriers are sometimes symptomatic with elevated VLCFA levels. Summary of Experimental Data (6 points): ALDP is shown to be reduced or absent in expression in patients with ABCD1 deficiency. Mice deficient in ALDP do not phenocopy the neurologic disturbances typical of childhood-onset ALD, but do exhibit VLCFA accumulation (PMID: 9256488, 7878038). However, mouse models do recapitulate the adult-onset AMN phenotype (11875044, 15489218). ALDP interacts with PEX19, another peroxisome membrane protein that is implicated in peroxisome biogenesis disorders. Rescue in patient cells has been shown with expression of recombinant ALDP restoring peroxisome beta-oxidation. Lentiviral-mediated gene therapy in ALD patients has shown to mitigate major functional disabilities in childhood patients with ALD (PMID: 28976817). Blocking ABCD1 in healthy fibroblasts leads to VLCFA accumulation similar to that seen in patients with XALD (PMID: 23671276). In summary, *ABCD1* is definitively associated with adrenoleukodystrophy (ABCD1 deficiency). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Peroxisomal Disorders GCEP on December 18, 2020 (SOP Version 7).

adrenoleukodystrophySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0018544

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

AdrenoleukodystrophyXL

Manifestation: Biochemical; Endocrine; Neurologic

Intervention: Biochemical

Rationale: For individuals with adrenal insufficiency, corticosteroid treatment is indicated; In asymptomatic individuals with ALD, medical treatment (eg, with oleic and erucic acids) may be beneficial in combination with dietary measures, though the benefit of such treatment in other affected individuals, such as symptomatic individuals, may not warrant such treatment; BMT/HSCT has been reported as effective if performed early, and gene therapy has been approved to treat some forms of the condition

Refs: 169765; 61263; 965973; 200861; 200862; 218453; 7438498; 7436359; 6299222; 7202134; 6280106; 6387532; 2682348; 2309698; 7904210; 8094785; 8338333; 8441467; 7849723; 8040304; 7581394; 7825602; 8566952; 8636252; 9062496; 9183487; 10073906; 9894883; 11748843; 11085690; 11204280; 11916318; 11220738; 12210797; 12486501; 12913200; 15073029; 15812458; 16240348; 15668429; 16305618; 16380594; 16009761; 16313334; 17372139; 17353371; 18759549; 19892975; 20301491; 28976817Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ABCD1 variants in ClinVar

24 Conditions Cataloged
AdrenoleukodystrophyTotal: 1480
not providedTotal: 510
Inborn genetic diseasesTotal: 137
not specifiedTotal: 90
ABCD1-related disorderTotal: 77
X-linked cerebral adrenoleukodystrophyTotal: 2
Primary adrenocortical insufficiencyTotal: 2
Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000033.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
1
clinvar
10
clinvar
362
clinvar
20
clinvar
 394
missense
68
clinvar
235
clinvar
429
clinvar
100
clinvar
11
clinvar
 843
nonsense
58
clinvar
11
clinvar
5
clinvar
 74
start loss
3
clinvar
 3
frameshift
116
clinvar
44
clinvar
4
clinvar
 164
splice donor/acceptor (+/-2bp)
31
clinvar
17
clinvar
3
clinvar
 51
Total277308451462311529

Highest pathogenic variant AF is 0.00003572571

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000033.4RefSeqNP_000024.210MANE Select
ENST00000218104.6EnsemblENSP00000218104.310MANE Select
NM_001440747.1RefSeqNP_001427676.111Standard
ENST00000370129.4EnsemblENSP00000359147.32Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
abcd1Danio rerio

Structure: whole organism

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Peroxisome - Homo sapiens (human)
  • ABC transporters - Homo sapiens (human)
  • Beta Oxidation of Very Long Chain Fatty Acids
  • Oxidation of Branched Chain Fatty Acids
  • Refsum Disease

Biological Process

  • regulation of oxidative phosphorylation
  • fatty acid beta-oxidation
  • peroxisome organization
  • peroxisomal long-chain fatty acid import
  • fatty-acyl-CoA transport

Molecular Function

  • transporter activity
  • long-chain fatty acid transporter activity
  • protein binding
  • ATP binding
  • fatty-acyl-CoA transmembrane transporter activity

Cellular Component

  • cytoplasm
  • lysosomal membrane
  • peroxisome
  • peroxisomal membrane
  • integral component of peroxisomal membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000218104
Coding exons
10
Length
19894
Individuals with no LoFs
108694
Homozygous LoFs
1
Heterozygous LoFs
1
Defined
108696
p
0.00000920
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.872503480.7190.00003284682
Missense (PolyPhen)46115.360.398761535
Synonymous0.4411511580.9550.00001531619
Loss of Function4.13019.90.000.00000134331

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000300.000021rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Plays a role in the transport of free very-long-chain fatty acids (VLCFAs) as well as their CoA-esters across the peroxisomal membrane by acting as an ATP-specific binding subunit releasing ADP after ATP hydrolysis (PubMed:15682271, PubMed:11248239, PubMed:16946495). Thus, plays a role in regulation of VLCFAs and energy metabolism namely, in the degradation and biosynthesis of fatty acids by beta-oxidation, mitochondrial function and microsomal fatty acid elongation (PubMed:23671276). Involved in several processes; namely, controls the active myelination phase by negatively regulating the microsomal fatty acid elongation activity and may also play a role in axon and myelin maintenance. Controls also the cellular response to oxidative stress by regulating mitochondrial function like, mitochondrial oxidative phosphorylation and depolarization. And finally controls the inflammatory response by positively regulating peroxisomal beta-oxidation of VLCFAs (By similarity). {ECO:0000250|UniProtKB:P48410, ECO:0000269|PubMed:11248239, ECO:0000269|PubMed:15682271, ECO:0000269|PubMed:16946495, ECO:0000269|PubMed:23671276}.;
Disease
DISEASE: Adrenoleukodystrophy (ALD) [MIM:300100]: A peroxisomal metabolic disorder characterized by progressive multifocal demyelination of the central nervous system and by peripheral adrenal insufficiency (Addison disease). It results in mental deterioration, corticospinal tract dysfunction, and cortical blindness. Different clinical manifestations exist like: cerebral childhood ALD (CALD), adult cerebral ALD (ACALD), adrenomyeloneuropathy (AMN) and 'Addison disease only' (ADO) phenotype. {ECO:0000269|PubMed:10369742, ECO:0000269|PubMed:10480364, ECO:0000269|PubMed:10551832, ECO:0000269|PubMed:10737980, ECO:0000269|PubMed:10980539, ECO:0000269|PubMed:11248239, ECO:0000269|PubMed:11438993, ECO:0000269|PubMed:11810273, ECO:0000269|PubMed:15643618, ECO:0000269|PubMed:21700483, ECO:0000269|PubMed:21889498, ECO:0000269|PubMed:23651979, ECO:0000269|PubMed:26686776, ECO:0000269|PubMed:7581394, ECO:0000269|PubMed:7717396, ECO:0000269|PubMed:7825602, ECO:0000269|PubMed:7849723, ECO:0000269|PubMed:7904210, ECO:0000269|PubMed:8040304, ECO:0000269|PubMed:8566952, ECO:0000269|PubMed:8651290, ECO:0000269|PubMed:9452087}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=The promoter region of ABCD1 is deleted in the chromosome Xq28 deletion syndrome which involves ABCD1 and the neighboring gene BCAP31. {ECO:0000269|PubMed:11992258}.;

Recessive Scores

pRec
0.769

Intolerance Scores

LoFtool
0.0188
RVIS EVS
-0.54
RVIS percentile EVS
20.54

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.783

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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