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GNPAT
glyceronephosphate O-acyltransferase
The GNPAT gene provides instructions for an enzyme called glyceronephosphate O-acyltransferase (GNPAT), which plays a key role in the production of specific lipids called plasmalogens within cellular peroxisomes. GNPAT is essential for the first step in synthesising plasmalogens, a type of lipid found in cell membranes and myelin.
GNPAT is located on the long (q) arm of chromosome 1, at band 1q42.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The GNPAT gene encodes the enzyme glyceronephosphate O-acyltransferase (GNPAT), also known as dihydroxyacetonephosphate acyltransferase (DHAPAT). This enzyme is located within peroxisomes, which are cellular compartments responsible for breaking down various substances and producing specific fats (lipids). GNPAT is crucial for initiating the synthesis of plasmalogens, a class of lipids important for cell membrane structure and nerve cell insulation.
What the gene does
The GNPAT enzyme, found in peroxisomes, catalyses the initial step in the biosynthesis of plasmalogens. Plasmalogens are unique lipid molecules that are abundant in cell membranes throughout the body, particularly in the myelin sheath that insulates nerve cells. While their precise functions are still under investigation, plasmalogens are thought to contribute to cellular protection against oxidative stress, a process where unstable molecules called free radicals can damage cells. They may also be involved in interactions between lipids and proteins, the transmission of chemical signals within cells, and the fusion of cell membranes. A deficiency in functional GNPAT enzyme disrupts peroxisome activity and significantly reduces cellular plasmalogen levels, impacting these critical cellular processes.
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Chromosome location
The GNPAT gene is located on chromosome 1, specifically at position 1q42.2. This indicates its position on the long arm (q) of chromosome 1, within region 42, band 2.
Protein structure
The GNPAT protein consists of 680 amino acids. It features a HXXXXD motif located between amino acids 162 and 167, which is a conserved sequence often found in acyltransferase enzymes. Additionally, a Microbody targeting signal is present at amino acids 678-680, which is responsible for directing the protein to peroxisomes.
Key variants
Genetic variations within the GNPAT gene can lead to altered enzyme function, ranging from reduced activity to a complete loss of function. These changes can disrupt the normal production of plasmalogens and impair peroxisome 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.1158G>A | p.Trp386Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Rhizomelic chondrodysplasia punctata type 2 |
c.1429_1430del | p.Met477fs | Pathogenic | ★★☆☆ | Rhizomelic chondrodysplasia punctata type 2 |
c.1483del | p.Leu494_Val495insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Rhizomelic chondrodysplasia punctata type 2 |
c.1583_1586del | p.Leu528fs | Pathogenic | ★★☆☆ | Rhizomelic chondrodysplasia punctata |
c.180T>A | p.Tyr60Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Rhizomelic chondrodysplasia punctata type 2 |
c.487C>T | p.Arg163Ter | Pathogenic | ★★☆☆ | Rhizomelic chondrodysplasia punctata type 2 |
c.569-3T>G | - | Pathogenic | ★★☆☆ | GNPAT-related disorders |
c.574del | p.Leu192fs | Pathogenic/Likely pathogenic | ★★☆☆ | Rhizomelic chondrodysplasia punctata type 2 |
c.632G>A | p.Arg211His | Pathogenic | ★★☆☆ | Rhizomelic chondrodysplasia punctata type 2 |
c.849_850dup | p.Tyr284fs | Pathogenic | ★★☆☆ | Rhizomelic chondrodysplasia punctata type 2 |
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 GNPAT gene are associated with inherited metabolic disorders, particularly those affecting peroxisome biogenesis and function. These conditions often manifest with a range of symptoms related to impaired lipid metabolism and cellular dysfunction.
No disease links recorded for this gene in our reference set.
UK clinical status
The GNPAT gene is included in several UK NHS national genomic testing panels, indicating its clinical relevance in the UK. It is listed as 'green' (gene has strong evidence of association with the disease) on PanelApp UK for conditions such as Bilateral congenital or childhood onset cataracts, Chondrodysplasia punctata, Foetal anomalies, Intellectual disability, Peroxisomal disorders, Skeletal dysplasia, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the GNPAT gene?
The GNPAT gene provides instructions for making an enzyme crucial for the first step in synthesising plasmalogens, which are special lipids found in cell membranes and nerve insulation. This enzyme operates within cellular compartments called peroxisomes.
What are plasmalogens and why are they important?
Plasmalogens are a type of lipid molecule found extensively in cell membranes and myelin, the protective sheath around nerve cells. They are thought to help protect cells from damage caused by oxidative stress and play roles in cell signalling and membrane interactions.
What happens if the GNPAT gene doesn't work correctly?
If the GNPAT gene is not functioning properly, it can lead to a shortage of the GNPAT enzyme. This disrupts the production of plasmalogens and impairs the normal function of peroxisomes, which can result in various health conditions affecting lipid metabolism and cellular processes.
References
- Liu D, Nagan N, Just WW. Role of dihydroxyacetonephosphate acyltransferase in the biosynthesis of plasmalogens and nonether glycerolipids. Journal of lipid research. 2005. PMID: 15687349
- Thai TP, Rodemer C, Jauch A. Impaired membrane traffic in defective ether lipid biosynthesis. Human molecular genetics. 2001. PMID: 11152660
- Ofman R, Lajmir S, Wanders RJ. Etherphospholipid biosynthesis and dihydroxyactetone-phosphate acyltransferase: resolution of the genomic organization of the human gnpat gene and its use in the identification of novel mutations. Biochemical and biophysical research communications. 2001. PMID: 11237722
- Ofman R, Hettema EH, Hogenhout EM. Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2. Human molecular genetics. 1998. PMID: 9536089
- Wanders RJ, Schumacher H, Heikoop J. Human dihydroxyacetonephosphate acyltransferase deficiency: a new peroxisomal disorder. Journal of inherited metabolic disease. 1992. PMID: 1405476