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CYP4F22
cytochrome P450 family 4 subfamily F member 22
CYP4F22 is located on the short (p) arm of chromosome 19, at band 19p13.12. Arm ratio per GRCh38 - banding schematic.
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Overview
CYP4F22 encodes cytochrome P450 family 4 subfamily F member 22, an enzyme that functions within the epidermis to support the formation and maintenance of the skin barrier. The protein is expressed predominantly in keratinocytes, the cells that make up the outermost layers of the skin, where it participates in the metabolism of fatty acids and related lipid molecules essential for normal barrier integrity.
Pathogenic variants in CYP4F22 follow an autosomal recessive inheritance pattern, meaning that both copies of the gene must carry a disease-causing change for clinical features to manifest. Loss of CYP4F22 function impairs the formation of specialised lipid structures in the stratum corneum, the skin's outermost layer, resulting in conditions characterised by abnormal scaling and compromised barrier function.
What the gene does
The CYP4F22 protein belongs to the cytochrome P450 superfamily, a diverse group of haem-containing enzymes that catalyse oxidation reactions across numerous metabolic pathways. CYP4F22 exhibits omega-hydroxylase activity, meaning it adds a hydroxyl group to the terminal carbon of fatty acid chains. This enzymatic modification is particularly important for the metabolism of ultra-long-chain fatty acids found in ceramides, complex lipid molecules that are essential structural components of the skin barrier.
Within keratinocytes, CYP4F22 contributes to the processing of acylceramides, specialised lipids that undergo enzymatic modification before being incorporated into the lipid lamellae of the stratum corneum. These tightly organised lipid layers create a hydrophobic barrier that prevents excessive water loss and protects against external insults. When CYP4F22 function is absent or reduced, the normal assembly of these lipid structures is disrupted, compromising the skin's ability to regulate hydration and maintain its defensive properties.
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Chromosome location
CYP4F22 is located on the short arm of chromosome 19 at position 13.12, designated as 19p13.12. This chromosomal region contains a cluster of related cytochrome P450 genes, reflecting the evolutionary expansion of this enzyme family. The gene spans multiple exons that encode a 531-amino-acid protein, though detailed exon-intron architecture has not been comprehensively catalogued in public databases.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. As a member of the cytochrome P450 superfamily, CYP4F22 is expected to share the characteristic structural features common to these enzymes, including a haem-binding domain that coordinates the iron-containing porphyrin ring essential for catalytic activity. However, specific domain boundaries and functional motifs unique to CYP4F22 have not been annotated in reference protein databases.
Key variants
Pathogenic variants in CYP4F22 have been identified in individuals with autosomal recessive congenital ichthyosis and related conditions affecting skin barrier function. The variant spectrum includes missense changes that impair enzymatic activity, nonsense variants that introduce premature stop codons, and frameshift alterations caused by small insertions or deletions. Because the gene follows an autosomal recessive inheritance pattern, affected individuals typically carry pathogenic variants on both copies of the gene, either as homozygous changes or compound heterozygous combinations.
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.1084C>T | p.Arg362Ter | Pathogenic | ★★☆☆ | Lamellar ichthyosis |
c.1085G>A | p.Arg362Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Lamellar ichthyosis |
c.1351C>T | p.Arg451Cys | Pathogenic/Likely pathogenic | ★★☆☆ | CYP4F22-related disorder |
c.177C>G | p.Phe59Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Lamellar ichthyosis |
c.296G>A | p.Trp99Ter | Pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 5 |
c.429dup | p.Leu144fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 5 |
c.466C>T | p.Arg156Cys | Pathogenic | ★★☆☆ | CYP4F22-related disorder |
c.59dup | p.Ile21fs | Pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 5 |
c.667C>T | p.Gln223Ter | Pathogenic | ★★☆☆ | CYP4F22-related disorder |
c.727C>T | p.Arg243Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Lamellar ichthyosis |
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 CYP4F22 are associated with autosomal recessive congenital ichthyosis, a group of inherited skin disorders characterised by abnormal scaling and thickening of the skin. Clinical manifestations range from milder forms with generalised fine scaling to more severe presentations with pronounced hyperkeratosis and impaired barrier function. The underlying mechanism involves disrupted lipid metabolism in the stratum corneum, which compromises the skin's ability to retain moisture and provide effective protection against environmental challenges. Individuals with CYP4F22-related ichthyosis may also experience increased susceptibility to skin infections and difficulties with temperature regulation due to the compromised barrier.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic CYP4F22 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
CYP4F22 appears on multiple NHS Genomic Medicine Service panels related to skin disorders, reflecting its clinical importance in the diagnosis of inherited ichthyoses. The gene holds green classification status on the Autosomal recessive congenital ichthyosis panel, the Ichthyosis and erythrokeratoderma panel (R165), and the Palmoplantar keratodermas panel (R166), indicating strong evidence for its role in these conditions. CYP4F22 is also included on the Fetal anomalies panel (R21) with green status, as severe forms of congenital ichthyosis may be detected prenatally through imaging or postnatal examination.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is CYP4F22-related ichthyosis inherited?
CYP4F22-related ichthyosis follows an autosomal recessive pattern, meaning an individual must inherit a pathogenic variant from both parents to be affected. Parents who each carry one variant are typically unaffected carriers.
What does CYP4F22 do in the skin?
CYP4F22 encodes an enzyme that modifies ultra-long-chain fatty acids in ceramides, specialised lipids that form the water-resistant barrier in the outermost layer of skin. This enzymatic activity is essential for normal barrier function and hydration regulation.
Can CYP4F22 variants be detected through genetic testing?
Yes, pathogenic variants in CYP4F22 can be identified through clinical genetic testing, typically using sequencing panels designed for inherited skin disorders. Such testing is generally arranged through specialist dermatology or clinical genetics services.