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PHYH
phytanoyl-CoA 2-hydroxylase
The PHYH gene encodes an enzyme crucial for the alpha-oxidation pathway, responsible for breaking down phytanic acid within peroxisomes. The PHYH gene provides instructions for phytanoyl-CoA hydroxylase, an enzyme vital for peroxisome function.
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, or phytanoyl-CoA 2-hydroxylase, plays a central role in human metabolism, particularly in the breakdown of certain fatty acids. It encodes an enzyme that facilitates the alpha-oxidation of phytanic acid, a branched-chain fatty acid derived from the diet.
This gene is fundamental for the proper functioning of peroxisomes, which are cellular organelles containing enzymes that break down various substances. Understanding PHYH is key to comprehending metabolic disorders linked to phytanic acid accumulation.
What the gene does
The PHYH gene directs the synthesis of phytanoyl-CoA hydroxylase, an enzyme critical for the normal operation of peroxisomes. Peroxisomes are specialised compartments within cells that contain enzymes necessary for metabolising fatty acids and detoxifying certain compounds.
Phytanoyl-CoA hydroxylase performs one of the initial steps in breaking down phytanic acid, a fatty acid obtained from dietary sources such as beef and dairy products. This process, known as alpha-oxidation, converts phytanic acid into smaller molecules that the body can then utilise for energy. Researchers also suggest that phytanoyl-CoA hydroxylase may have additional functions, including regulating the number and activity of peroxisomes within cells.
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Chromosome location
The PHYH gene is situated on chromosome 10, specifically at position 10p13. This location refers to the short (p) arm of chromosome 10, within band 13. The gene's position on this chromosome helps define its genomic context.
Protein structure
The PHYH gene codes for a protein consisting of 338 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations within the PHYH gene can influence the structure or production of the phytanoyl-CoA hydroxylase enzyme. These alterations may lead to reduced enzyme activity, disrupting the normal breakdown of phytanic acid within the body. Approximately 30 different genetic changes have been identified in this gene.
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.127C>T | p.Gln43Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.133C>T | p.Gln45Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PHYH-related disorder |
c.135-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.375_376del | p.Glu126fs | Pathogenic/Likely 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.520del | p.Leu174fs | Pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.520dup | p.Leu174fs | Pathogenic/Likely pathogenic | ★★☆☆ | Phytanic acid storage disease |
c.675G>A | p.Trp225Ter | 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
Variants in the PHYH gene are strongly associated with metabolic disorders, particularly those involving the accumulation of phytanic acid. When the phytanoyl-CoA hydroxylase enzyme is deficient or non-functional, phytanic acid cannot be properly broken down. This leads to its build-up in tissues and organs, which can cause a range of health issues.
No disease links recorded for this gene in our reference set.
UK clinical status
The PHYH gene is included in several UK NHS national genomic test directories. It is listed as 'green' on PanelApp for Hereditary neuropathy, Hereditary neuropathy or pain disorder (R78), Likely inborn error of metabolism (R98), Peroxisomal disorders, and Retinal disorders (R32). A 'green' status indicates that there is sufficient evidence to support the gene's association with these conditions for diagnostic purposes.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the PHYH gene?
The PHYH gene provides instructions for creating an enzyme called phytanoyl-CoA hydroxylase. This enzyme is crucial for the initial breakdown of phytanic acid, a fatty acid, within peroxisomes through a process called alpha-oxidation.
What happens if the PHYH gene doesn't work correctly?
If the PHYH gene is not functioning properly, the enzyme it codes for may be deficient or inactive. This can lead to the accumulation of phytanic acid in the body, as its breakdown pathway is disrupted.
Where does phytanic acid come from?
Phytanic acid is a type of fatty acid primarily obtained through the diet. It is found in certain foods, particularly from sources like beef and dairy products.
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