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ABCA12
ATP binding cassette subfamily A member 12
The ABCA12 gene provides instructions for an ATP-binding cassette (ABC) transporter protein crucial for lipid transport in skin cells and normal skin development. ABCA12 is a gene that codes for an ABC transporter protein.
ABCA12 is located on the long (q) arm of chromosome 2, at band 2q35. Arm ratio per GRCh38 - banding schematic.
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Overview
The ABCA12 gene, or ATP binding cassette subfamily A member 12, plays a significant role in human health by directing the production of an ATP-binding cassette (ABC) transporter protein. These proteins are known for their ability to transport various molecules across cell membranes. Specifically, the ABCA12 protein is critical for lipid and enzyme transport within the epidermis, the outermost layer of the skin. This transport mechanism is fundamental for the development and maintenance of healthy skin, helping to regulate hydration and overall skin integrity.
What the gene does
The ABCA12 protein acts as an ABC transporter, facilitating the movement of lipids and enzymes within the cells of the epidermis. This transport activity is essential for forming and maintaining the layered structure of lipids within the skin, which serves as a protective barrier against water loss. Without proper function of the ABCA12 protein, these vital molecules cannot be moved efficiently, leading to disruptions in skin development and barrier function. The protein's role in lipid transport is therefore key to preventing dehydration and ensuring the skin's overall health.
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Chromosome location
The ABCA12 gene is located on chromosome 2, specifically at position 2q35. This genomic location indicates where the gene can be found within the human genome. The gene's position is important for understanding its context relative to other genes and its potential involvement in chromosomal rearrangements.
Protein structure
The ABCA12 protein is 2595 amino acids long and contains several distinct functional regions. It features two prominent ABC transporter domains: ABC transporter 1, located between amino acids 1346 and 1577, and ABC transporter 2, found between amino acids 2254 and 2489. Additionally, a disordered region is present at the C-terminus, spanning amino acids 2571 to 2595. These domains collectively contribute to the protein's ability to transport molecules.
Key variants
Variants within the ABCA12 gene can impact the structure and function of the encoded protein, potentially disrupting its role in lipid transport. Many identified genetic changes lead to the production of an abnormally short or non-functional protein. These alterations can have significant consequences for skin development and its barrier function.
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.1210C>T | p.Arg404Ter | Pathogenic | ★★☆☆ | not provided |
c.1300C>T | p.Arg434Ter | Pathogenic | ★★☆☆ | not provided |
c.1583del | p.Asn528fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 4A |
c.178C>T | p.Arg60Ter | Pathogenic | ★★☆☆ | not provided |
c.179G>C | p.Arg60Pro | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.2140C>T | p.Arg714Ter | Pathogenic | ★★☆☆ | not provided |
c.2273dup | p.Leu758fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.2296C>T | p.Gln766Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.2956C>T | p.Arg986Trp | Pathogenic | ★★☆☆ | Lamellar ichthyosis |
c.3256A>T | p.Lys1086Ter | Pathogenic | ★★☆☆ | not provided |
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
Genetic changes in the ABCA12 gene are associated with several inherited skin conditions, including Harlequin ichthyosis, a severe form of ichthyosis characterised by thick, plate-like scales present at birth. Other conditions linked to ABCA12 variants include nonbullous congenital ichthyosiform erythroderma and lamellar ichthyosis, both of which also involve abnormalities in skin texture and integrity, though typically less severe than Harlequin ichthyosis.
Inheritance pattern
Conditions caused by pathogenic ABCA12 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
The ABCA12 gene is included in several NHS Genomic Medicine Service national test directories. It is listed as 'green' for autosomal recessive congenital ichthyosis, foetal anomalies (R21), ichthyosis and erythrokeratoderma (R165), and palmoplantar keratodermas (R166), indicating that it is considered diagnostically relevant for these conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ABCA12 gene?
The ABCA12 gene provides instructions for an ATP-binding cassette (ABC) transporter protein. This protein is essential for transporting lipids and enzymes within epidermal cells, which is crucial for normal skin development and maintaining the skin's barrier function.
What conditions are associated with variants in the ABCA12 gene?
Variants in the ABCA12 gene are associated with several inherited skin disorders, including Harlequin ichthyosis, nonbullous congenital ichthyosiform erythroderma, and lamellar ichthyosis. These conditions primarily affect the skin's texture, integrity, and barrier function.
How does ABCA12 relate to skin health?
The ABCA12 protein helps transport lipids and enzymes that are necessary for the formation and maintenance of the skin's outermost layer, the epidermis. Proper lipid layering is vital for preventing water loss and ensuring the skin acts as an effective protective barrier.
References
- Nawaz S, Tariq M, Ahmad I. Non-bullous congentital ichthyosiform erythroderma associated with homozygosity for a novel missense mutation in an ATP binding domain of ABCA12. European journal of dermatology : EJD. 2012. PMID: 22257947
- Sakai K, Akiyama M, Yanagi T. ABCA12 is a major causative gene for non-bullous congenital ichthyosiform erythroderma. The Journal of investigative dermatology. 2009. PMID: 19262603
- Thomas AC, Cullup T, Norgett EE. ABCA12 is the major harlequin ichthyosis gene. The Journal of investigative dermatology. 2006. PMID: 16902423
- Kelsell DP, Norgett EE, Unsworth H. Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. American journal of human genetics. 2005. PMID: 15756637
- Lefévre C, Audebert S, Jobard F. Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Human molecular genetics. 2003. PMID: 12915478
- Adam MP, Bick S, Mirzaa GM. Autosomal Recessive Congenital Ichthyosis. 1993. PMID: 20301593