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PHYH
phytanoyl-CoA 2-hydroxylase
The *PHYH* gene provides instructions for producing phytanoyl-CoA hydroxylase, an enzyme crucial for breaking down phytanic acid within cellular structures called peroxisomes. The *PHYH* gene is vital for metabolic processes, particularly in the breakdown of phytanic acid, a fatty acid obtained through diet.
PHYH is located on the short (p) arm of chromosome 10, at band 10p13. Arm ratio per GRCh38 - banding schematic.
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Overview
The *PHYH* gene encodes an enzyme known as phytanoyl-CoA hydroxylase, which plays a key role in cellular metabolism. This enzyme is primarily active within peroxisomes, which are specialised compartments in cells responsible for processing various substances, including fatty acids and certain toxic compounds.
Phytanoyl-CoA hydroxylase is particularly important for initiating the breakdown of phytanic acid, a type of fatty acid derived from the diet. The proper function of this enzyme is critical for preventing the accumulation of phytanic acid in the body.
What the gene does
The phytanoyl-CoA hydroxylase enzyme, encoded by the *PHYH* gene, is essential for a metabolic pathway called alpha-oxidation. This process specifically targets phytanic acid, a branched-chain fatty acid found in foods such as beef and dairy products. The enzyme catalyses one of the initial steps in breaking down phytanic acid within peroxisomes.
Following this initial step, other enzymes further process phytanic acid into smaller molecules that the body can utilise for energy. Beyond its direct role in phytanic acid metabolism, research suggests that phytanoyl-CoA hydroxylase might also influence the number and activity of peroxisomes within cells, indicating broader regulatory functions.
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Chromosome location
The *PHYH* gene is located on chromosome 10, specifically at position 10p13. This genetic locus contains the instructions for synthesising the phytanoyl-CoA hydroxylase enzyme, which consists of 338 amino acids.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations within the *PHYH* gene can alter the function or production of the phytanoyl-CoA hydroxylase enzyme. These changes may reduce the enzyme's activity, leading to impaired metabolic processes.
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.135-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.375_376del | p.Glu126fs | Pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.426del | p.Lys141_Tyr142insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.457del | p.Ala153fs | Pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.497-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Retinal dystrophy |
c.520dup | p.Leu174fs | Pathogenic/Likely pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.675G>A | p.Trp225Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.679-1dup | - | Pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.811del | p.Thr271fs | Pathogenic/Likely pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.830C>A | p.Ala277Glu | Pathogenic/Likely pathogenic | ★★☆☆ | Phytanic acid storage disease |
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 the *PHYH* gene are a primary cause of Refsum disease. This condition is characterised by the impaired breakdown of phytanic acid, leading to its accumulation in tissues and organs throughout the body.
No disease links recorded for this gene in our reference set.
UK clinical status
The *PHYH* gene is included in several NHS England Genomic Medicine Service approved panels. These panels cover various inherited conditions, including Hereditary neuropathy, Hereditary neuropathy or pain disorder (R78), Likely inborn error of metabolism (R98), Peroxisomal disorders, and Retinal disorders (R32), indicating its recognised clinical significance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is phytanic acid?
Phytanic acid is a type of branched-chain fatty acid that is primarily obtained through diet, particularly from foods like beef and dairy products. It requires a specific metabolic pathway, initiated by the PHYH enzyme, for its breakdown in the body.
What are peroxisomes?
Peroxisomes are small, membrane-bound organelles found within cells. They contain enzymes that are responsible for various metabolic functions, including the breakdown of fatty acids, amino acids, and detoxification of certain substances.
How do *PHYH* gene variants affect the body?
Variants in the *PHYH* gene can reduce the activity of the phytanoyl-CoA hydroxylase enzyme, leading to a build-up of phytanic acid in the body. This accumulation can cause damage to various tissues and organs, contributing to symptoms seen in conditions like Refsum disease.
References
- Wanders RJ, Komen JC. Peroxisomes, Refsum's disease and the alpha- and omega-oxidation of phytanic acid. Biochemical Society transactions. 2007. PMID: 17956234
- van den Brink DM, Wanders RJ. Phytanic acid: production from phytol, its breakdown and role in human disease. Cellular and molecular life sciences : CMLS. 2006. PMID: 16799769
- McDonough MA, Kavanagh KL, Butler D. Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease. The Journal of biological chemistry. 2005. PMID: 16186124
- Jansen GA, Waterham HR, Wanders RJ. Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7). Human mutation. 2004. PMID: 14974078
- Mukherji M, Chien W, Kershaw NJ. Structure-function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum's disease. Human molecular genetics. 2001. PMID: 11555634
- Jansen GA, Hogenhout EM, Ferdinandusse S. Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease. Human molecular genetics. 2000. PMID: 10767344
- Jansen GA, Wanders RJ, Watkins PA. Phytanoyl-coenzyme A hydroxylase deficiency -- the enzyme defect in Refsum's disease. The New England journal of medicine. 1997. PMID: 9221344
- Mihalik SJ, Morrell JC, Kim D. Identification of PAHX, a Refsum disease gene. Nature genetics. 1997. PMID: 9326939
- Jansen GA, Ofman R, Ferdinandusse S. Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nature genetics. 1997. PMID: 9326940
- Adam MP, Bick S, Mirzaa GM. Adult Refsum Disease. 1993. PMID: 20301527