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ACSL4
acyl-CoA synthetase long chain family member 4
ACSL4 encodes an enzyme that activates long-chain fatty acids for incorporation into cellular lipids, with variants linked to X-linked intellectual disability. The ACSL4 gene produces an enzyme responsible for attaching coenzyme A to long-chain fatty acids, a critical step for building and remodelling cell membranes.
ACSL4 is located on the long (q) arm of chromosome X, at band Xq23. Arm ratio per GRCh38 - banding schematic.
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Overview
ACSL4 encodes acyl-CoA synthetase long-chain family member 4, an enzyme that catalyses the activation of long-chain fatty acids by linking them to coenzyme A. This activation step is essential for incorporating fatty acids into phospholipids, the structural components of cell membranes. The gene resides on the X chromosome, and pathogenic changes predominantly affect males due to hemizygosity. Loss of ACSL4 function impairs membrane composition and cellular signalling, with particularly pronounced effects in the developing nervous system. The condition is recognised in UK clinical genomics pathways for intellectual disability assessment.
What the gene does
ACSL4 catalyses the conversion of long-chain fatty acids-particularly arachidonic acid and other polyunsaturated fatty acids-into their acyl-CoA derivatives. These activated fatty acids serve as substrates for incorporation into phospholipids, which form the bilayer structure of all cellular membranes. ACSL4 plays a selective role in arachidonic acid metabolism, influencing the composition of membrane lipids in neurons and other cells. By controlling which fatty acids enter lipid biosynthetic pathways, the enzyme affects membrane fluidity, receptor function, and intracellular signalling. The protein localises to the endoplasmic reticulum and mitochondria-associated membranes, positioning it at key sites for lipid synthesis and remodelling. Disruption of ACSL4 activity alters the balance of polyunsaturated fatty acids in brain tissue, which is thought to underlie the neurodevelopmental features observed in affected individuals.
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Chromosome location
ACSL4 is located on the long arm of the X chromosome at band Xq23. The gene spans multiple exons encoding a 711-amino-acid protein. Its position on the X chromosome means that males inherit only one copy, making them more vulnerable to loss-of-function variants. Females typically carry two X chromosomes and may exhibit variable expression depending on X-inactivation patterns.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Pathogenic variants in ACSL4 include loss-of-function changes such as nonsense mutations, frameshifts, and deletions that abolish enzyme activity. Missense variants affecting conserved residues within the catalytic core can also impair substrate binding or enzymatic function. The majority of reported pathogenic variants are found in males presenting with intellectual disability, though carrier females may occasionally show mild features due to skewed X-inactivation.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
GRCh37/hg19 Xq23(chrX:108919564-108929311) | - | Pathogenic | ★☆☆☆ | Ischemic stroke |
c.1235dup | p.Met413fs | Pathogenic | ★☆☆☆ | Intellectual disability, X-linked 63 |
c.727C>T | p.Arg243Ter | Pathogenic | ★☆☆☆ | not provided |
c.802del | p.Leu268fs | Pathogenic | ★☆☆☆ | Intellectual disability, X-linked 63 |
c.845_846del | p.His282fs | Pathogenic | ★☆☆☆ | not provided |
c.1003-2A>G | - | Pathogenic | - | Intellectual disability, X-linked 63 |
c.1585C>A | p.Arg529Ser | Pathogenic | - | Intellectual disability, X-linked 63 |
c.1001C>T | p.Pro334Leu | Likely pathogenic | ★☆☆☆ | Intellectual disability, X-linked 63 |
c.1072_1073del | p.Leu358fs | Likely pathogenic | ★☆☆☆ | Intellectual disability, X-linked 63 |
c.1315+1G>A | - | Likely pathogenic | ★☆☆☆ | Intellectual disability, X-linked 63 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in ACSL4 cause X-linked intellectual disability, characterised by developmental delay, learning difficulties, and variable neurological features. Affected males may present with delayed speech, motor coordination problems, and behavioural challenges. The severity of cognitive impairment ranges from mild to moderate. Some individuals exhibit additional features such as epilepsy or minor physical anomalies, though the core phenotype centres on neurodevelopmental delay.
No disease links recorded for this gene in our reference set.
UK clinical status
ACSL4 is included on the NHS Genomic Medicine Service Developmental Disorders Genotype-to-Phenotype (DDG2P) panel with green classification, indicating strong evidence for disease association. The gene also appears on the Intellectual Disability panel (R29, green rating), supporting its use in diagnostic testing for individuals with unexplained developmental delay and intellectual disability. These panel memberships guide UK laboratories in variant interpretation and reporting.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
Why does ACSL4 primarily affect males?
ACSL4 is located on the X chromosome, and males have only one copy. A single pathogenic variant therefore eliminates enzyme function, whereas females with two X chromosomes often retain some activity from the unaffected copy.
What is the role of fatty acid activation in the brain?
Activated fatty acids are incorporated into the phospholipids that form neuronal membranes. These lipids influence membrane fluidity, receptor signalling, and synaptic plasticity, all critical for normal brain development and cognitive function.
Can carrier females have symptoms?
Most female carriers are unaffected, but in rare cases skewed X-inactivation can lead to mild developmental or learning difficulties. Genetic counselling can clarify individual risks and inheritance patterns.