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FA2H
fatty acid 2-hydroxylase
The *FA2H* gene provides instructions for an enzyme crucial in modifying fatty acids, which are vital components for proper neurological function and myelin formation. The *FA2H* gene encodes the enzyme fatty acid 2-hydroxylase, which plays a critical role in the nervous system by hydroxylating fatty acids.
FA2H is located on the long (q) arm of chromosome 16, at band 16q23.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The *FA2H* gene contains the genetic code for an enzyme called fatty acid 2-hydroxylase. This enzyme is vital for altering fatty acids, which are fundamental building blocks of many lipids found in the body. Specifically, it adds a hydroxyl group to fatty acid chains, producing 2-hydroxylated fatty acids. These specialised fatty acids are crucial for the nervous system's proper structure and function, particularly for creating myelin.
What the gene does
The fatty acid 2-hydroxylase enzyme, produced from the *FA2H* gene, is responsible for a critical modification of fatty acids. It catalyses the attachment of a hydroxyl group (-OH) to the second carbon atom of a fatty acid chain. This process generates 2-hydroxylated fatty acids.
These modified fatty acids are particularly important for the synthesis of myelin, a protective, fatty layer that insulates nerve fibres. Myelin enables quick and efficient transmission of electrical signals throughout the nervous system. The areas of the brain and spinal cord that are rich in myelin are referred to as white matter. Therefore, effective functioning of the *FA2H* enzyme is essential for maintaining healthy myelin and ensuring proper nerve impulse conduction.
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Chromosome location
The *FA2H* gene is found on chromosome 16, specifically at position 16q23.1. This location refers to the long arm (q arm) of chromosome 16. It contains the genetic information for a protein consisting of 372 amino acids.
Protein structure
The FA2H protein, comprising 372 amino acids, features two distinct functional regions. It contains a Cytochrome b5 heme-binding domain, located between amino acids 8 and 86. Additionally, a prominent Fatty acid hydroxylase domain is present, spanning amino acids 219 to 361. These domains are critical for the enzyme's catalytic activity in fatty acid modification.
Key variants
Genetic changes within the *FA2H* gene can modify the activity of the fatty acid 2-hydroxylase enzyme. These variations can include single base pair changes, or larger deletions or insertions. Such genetic alterations may lead to reduced enzyme activity or the production of an enzyme that does not function correctly, thereby disrupting the normal production of 2-hydroxylated fatty acids and impacting myelin formation.
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.363+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 35 |
c.379C>T | p.Arg127Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 35 |
c.506+1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
c.589C>T | p.Arg197Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 35 |
c.704G>A | p.Arg235His | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 35 |
c.806G>A | p.Arg269His | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
c.822del | p.Val275fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 35 |
c.888del | p.Gly298fs | Pathogenic | ★★☆☆ | Spastic paraplegia |
c.911dup | p.Leu305fs | Pathogenic | ★★☆☆ | Hereditary spastic paraplegia 35 |
c.941_945del | p.Thr314fs | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
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
Variations in the *FA2H* gene are associated with several inherited neurological disorders, often characterised by progressive neurodegeneration. One notable condition is Spastic paraplegia type 35 (AR), an autosomal recessive disorder. These conditions typically involve problems with movement and vision that can begin in childhood or adolescence and may worsen over time.
- Spastic paraplegia type 35 Dedicated page coming soon
UK clinical status
The *FA2H* gene is included in several UK NHS Genomic Medicine Service national test panels, indicating its clinical relevance for diagnosing inherited conditions. It is part of panels for Ataxia and cerebellar anomalies - childhood onset, Dystonia, chorea or related movement disorder, childhood onset, Early onset dystonia, Hereditary neuropathy or pain disorder, Hereditary spastic paraplegia, Hereditary spastic paraplegia, adult onset, Hereditary spastic paraplegia, childhood onset, Likely inborn error of metabolism, Structural basal ganglia disorders, Undiagnosed metabolic disorders, and White matter disorders and cerebral calcification - childhood onset.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the FA2H gene?
The *FA2H* gene provides instructions for an enzyme called fatty acid 2-hydroxylase, which modifies fatty acids. These modified fatty acids are crucial for the proper formation of myelin, the protective covering around nerve cells.
What health conditions are associated with FA2H gene variants?
Variations in the *FA2H* gene are linked to inherited neurological conditions, including Spastic paraplegia type 35 (AR). These conditions typically affect movement and vision due to neurodegeneration.
Is FA2H testing available through the NHS?
Yes, the *FA2H* gene is assessed within several UK NHS Genomic Medicine Service national test panels, particularly those related to neurological disorders, metabolic conditions, and childhood-onset conditions.
References
- Gregory A, Hayflick SJ. Genetics of neurodegeneration with brain iron accumulation. Current neurology and neuroscience reports. 2011. PMID: 21286947
- Dick KJ, Eckhardt M, Paisán-Ruiz C. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Human mutation. 2010. PMID: 20104589
- Kruer MC, Paisán-Ruiz C, Boddaert N. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Annals of neurology. 2010. PMID: 20853438
- Schneider SA, Bhatia KP. Three faces of the same gene: FA2H links neurodegeneration with brain iron accumulation, leukodystrophies, and hereditary spastic paraplegias. Annals of neurology. 2010. PMID: 21031573
- Edvardson S, Hama H, Shaag A. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. American journal of human genetics. 2008. PMID: 19068277
- Alderson NL, Rembiesa BM, Walla MD. The human FA2H gene encodes a fatty acid 2-hydroxylase. The Journal of biological chemistry. 2004. PMID: 15337768
- Adam MP, Bick S, Mirzaa GM. Fatty Acid Hydroxylase-Associated Neurodegeneration. 1993. PMID: 21735565