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AGPAT2
1-acylglycerol-3-phosphate O-acyltransferase 2
The AGPAT2 gene provides instructions for an enzyme crucial in synthesising specific fats, playing a vital role in fat cell (adipocyte) development and overall lipid metabolism. AGPAT2 is essential for the production of glycerophospholipids and triacylglycerols, which are fundamental components of cell membranes and energy storage, respectively.
AGPAT2 is located on the long (q) arm of chromosome 9, at band 9q34.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The AGPAT2 gene, or 1-acylglycerol-3-phosphate O-acyltransferase 2, encodes an enzyme integral to lipid metabolism. This enzyme is widely expressed across various cells and tissues in the human body.
Its primary function is pivotal for the growth and maturation of adipocytes, the cells responsible for storing fat for energy. Adipose tissue, largely composed of adipocytes, is crucial for energy homeostasis and endocrine function.
What the gene does
The AGPAT2 enzyme is a key player in a metabolic pathway that produces two essential types of lipids: glycerophospholipids and triacylglycerols. Glycerophospholipids are fundamental building blocks of cell membranes and are involved in intracellular signalling processes. Triacylglycerols, also known as triglycerides, are stored within adipocytes as the body's primary energy reserve.
Specifically, the AGPAT2 enzyme facilitates a critical step in this pathway by converting lysophosphatidic acid (LPA) into phosphatidic acid (PA). Subsequent reactions utilise phosphatidic acid to synthesise both glycerophospholipids and triacylglycerols. This enzymatic activity is therefore central to maintaining lipid balance and proper adipocyte function.
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Chromosome location
The AGPAT2 gene is located on chromosome 9, specifically at position 9q34.3. This chromosomal location indicates its physical address within the human genome.
Protein structure
The AGPAT2 protein is composed of 278 amino acids. Key functional regions within the protein include the HXXXXD motif, spanning amino acids 98-103, and the EGTR motif, found at amino acids 172-175. These motifs are important for the protein's enzymatic activity.
Key variants
Genetic variations within the AGPAT2 gene can impact the enzyme's function, potentially leading to altered lipid metabolism and adipocyte development. These variants can range from single nucleotide changes to larger deletions or insertions, and their effects on protein function can vary significantly.
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.202C>T | p.Arg68Ter | Pathogenic | ★★☆☆ | Congenital generalized lipodystrophy type 1 |
c.335del | p.Pro112fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital generalized lipodystrophy type 1 |
c.369_372del | p.Leu124fs | Pathogenic | ★★☆☆ | Congenital generalized lipodystrophy type 1 |
c.377dup | p.Pro128fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital generalized lipodystrophy type 1 |
c.492+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital generalized lipodystrophy type 1 |
c.493-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital generalized lipodystrophy type 1 |
c.514G>A | p.Glu172Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital generalized lipodystrophy type 1 |
c.589-2A>G | - | Pathogenic | ★★☆☆ | AGPAT2-related disorder |
c.646A>T | p.Lys216Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital generalized lipodystrophy type 1 |
c.662-2A>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital generalized lipodystrophy type 1 |
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 AGPAT2 gene are associated with congenital lipodystrophy type 1, also known as Berardinelli-Seip congenital lipodystrophy type 1. This rare, inherited condition is characterised by a near-complete absence of adipose tissue, leading to a distinctive muscular appearance and various metabolic complications, including high triglyceride levels.
Inheritance pattern
Conditions caused by pathogenic AGPAT2 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 AGPAT2 gene is included in several NHS Genomic Medicine Service national panels. These include panels for 'Diabetes with additional phenotypes suggestive of a monogenic aetiology', 'Familial diabetes', 'Insulin resistance (including lipodystrophy)', and 'Severe insulin resistance and lipodystrophy syndromes'.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the AGPAT2 gene?
The AGPAT2 gene provides instructions for an enzyme that plays a crucial role in lipid metabolism, specifically in the synthesis of glycerophospholipids and triacylglycerols. This is vital for cell membrane formation and energy storage within adipocytes.
What condition is associated with AGPAT2 variants?
Variants in the AGPAT2 gene are linked to congenital lipodystrophy type 1. This is a rare genetic condition characterised by a severe lack of adipose (fat) tissue, leading to various metabolic issues.
How does AGPAT2 affect fat cells?
The AGPAT2 enzyme is essential for the proper growth and development of adipocytes, which are the body's fat-storing cells. Its activity is necessary for the production of lipids that are fundamental for both the structure of cell membranes and the storage of energy.
References
- Patni N, Garg A. Congenital generalized lipodystrophies--new insights into metabolic dysfunction. Nature reviews. Endocrinology. 2015. PMID: 26239609
- Agarwal AK. Lysophospholipid acyltransferases: 1-acylglycerol-3-phosphate O-acyltransferases. From discovery to disease. Current opinion in lipidology. 2012. PMID: 22777291
- Miranda DM, Wajchenberg BL, Calsolari MR. Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome. Clinical endocrinology. 2009. PMID: 19226263
- Gale SE, Frolov A, Han X. A regulatory role for 1-acylglycerol-3-phosphate-O-acyltransferase 2 in adipocyte differentiation. The Journal of biological chemistry. 2006. PMID: 16495223
- Magré J, Delépine M, Van Maldergem L. Prevalence of mutations in AGPAT2 among human lipodystrophies. Diabetes. 2003. PMID: 12765973
- Agarwal AK, Arioglu E, De Almeida S. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nature genetics. 2002. PMID: 11967537