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SLC27A4
solute carrier family 27 member 4
SLC27A4 is located on the long (q) arm of chromosome 9, at band 9q34.11. Arm ratio per GRCh38 - banding schematic.
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Overview
SLC27A4 belongs to the solute carrier family 27, a group of genes encoding fatty acid transport proteins that facilitate the movement of long-chain fatty acids into cells. The protein produced by this gene plays a specialised role in keratinocytes, the predominant cell type in the epidermis, where it supports the formation and maintenance of the skin's lipid barrier.
Pathogenic changes in SLC27A4 follow an autosomal recessive inheritance pattern, meaning affected individuals carry two altered copies of the gene. When fatty acid transport is impaired, the skin cannot properly construct its protective outer layer, resulting in congenital ichthyosis - a group of disorders characterised by dry, thickened, and scaly skin present from birth or early infancy.
What the gene does
The SLC27A4 protein functions as a fatty acid transport protein, enabling cells to import long-chain fatty acids from the extracellular environment. Once inside the cell, these fatty acids serve as building blocks for complex lipids that are essential components of cell membranes and, in the skin, contribute to the formation of the stratum corneum - the outermost protective layer of the epidermis.
In keratinocytes, SLC27A4 works alongside other lipid-processing enzymes to ensure adequate supplies of fatty acids for ceramide synthesis. Ceramides are lipid molecules that form a waterproof barrier preventing excessive moisture loss and protecting against environmental insults. The protein's transport activity is particularly critical during the terminal differentiation of keratinocytes, when cells undergo structural changes to form the cornified envelope that serves as the skin's first line of defence.
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Chromosome location
SLC27A4 is located on chromosome 9 at position 9q34.11, near the telomeric end of the long arm. This genomic region contains multiple genes involved in diverse cellular processes. The precise exon structure and transcript variants of SLC27A4 contribute to its tissue-specific expression pattern, with highest activity observed in skin and adipose tissue where fatty acid metabolism is particularly active.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The SLC27A4 protein comprises 643 amino acids and is predicted to contain multiple transmembrane segments that anchor it within the cell membrane, consistent with its role as a transporter. Structural modelling suggests the protein adopts a conformation that creates a channel or binding pocket for long-chain fatty acids, facilitating their passage across the lipid bilayer.
Key variants
Pathogenic variants in SLC27A4 are typically loss-of-function changes that reduce or eliminate the protein's ability to transport fatty acids. These include nonsense variants that introduce premature stop codons, frameshift variants arising from small insertions or deletions, and missense variants that disrupt critical functional regions. The distribution of pathogenic variants across the gene reflects the importance of multiple regions for proper protein folding and substrate binding.
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 |
|---|---|---|---|---|
c.1065del | p.Arg356fs | Pathogenic | ★★☆☆ | Ichthyosis prematurity syndrome |
c.1430T>A | p.Val477Asp | Pathogenic/Likely pathogenic | ★★☆☆ | SLC27A4-related disorder |
c.1447C>T | p.Gln483Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ichthyosis prematurity syndrome |
c.1504C>T | p.Arg502Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Lamellar ichthyosis |
c.1799_1800del | p.Glu600fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ichthyosis prematurity syndrome |
c.199C>T | p.Arg67Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ichthyosis prematurity syndrome |
c.1A>G | p.Met1Val | Pathogenic | ★★☆☆ | Ichthyosis prematurity syndrome |
c.504C>A | p.Cys168Ter | Pathogenic/Likely pathogenic | ★★☆☆ | SLC27A4-related disorder |
c.556+2T>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.899A>G | p.Gln300Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Ichthyosis prematurity syndrome |
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
Biallelic pathogenic variants in SLC27A4 cause autosomal recessive congenital ichthyosis, a skin disorder characterised by generalised scaling and thickening of the skin present from birth. The severity can range from mild cases with fine scaling to more pronounced presentations with thick, plate-like scales and associated skin inflammation. Some affected individuals may also experience palmoplantar keratoderma - thickening of the skin on the palms and soles. The condition results directly from impaired lipid barrier formation in the epidermis when fatty acid transport is compromised.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SLC27A4 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
SLC27A4 appears on multiple NHS Genomic Medicine Service gene panels with green (high evidence) classification. The gene is included in the Autosomal recessive congenital ichthyosis panel, the DDG2P developmental disorders panel, the Fetal anomalies panel (as R21), and the Ichthyosis and erythrokeratoderma panel (as R165). This green status indicates strong evidence supporting the gene-disease relationship and justifies its inclusion in diagnostic testing pathways for patients presenting with relevant clinical features within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is SLC27A4-related ichthyosis inherited?
SLC27A4-related ichthyosis follows an autosomal recessive pattern, meaning an affected individual inherits one pathogenic variant from each parent. Parents who each carry one variant typically show no symptoms but have a 25% chance with each pregnancy of having an affected child.
What does the SLC27A4 protein do in the skin?
The SLC27A4 protein transports long-chain fatty acids into keratinocytes, where they are used to build ceramides and other lipids that form the skin's protective barrier. Without adequate fatty acid transport, this barrier becomes defective, leading to the scaling and dryness characteristic of ichthyosis.
Are all SLC27A4 variants pathogenic?
No, many variants in SLC27A4 are benign changes that do not affect protein function. Only variants that significantly disrupt fatty acid transport - typically nonsense, frameshift, or certain missense changes - are considered pathogenic and associated with ichthyosis.