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AGPAT2
1-acylglycerol-3-phosphate O-acyltransferase 2
The AGPAT2 gene encodes an enzyme crucial for the synthesis of specific fats, playing a vital role in the growth and function of fat-storing cells (adipocytes). AGPAT2 is involved in metabolic pathways that produce glycerophospholipids and triacylglycerols, which are fundamental components of cell membranes and energy storage.
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 provides instructions for producing 1-acylglycerol-3-phosphate O-acyltransferase 2, an enzyme found in many cell types and tissues throughout the body. This enzyme is critically involved in the development and growth of adipocytes, which are specialised cells responsible for storing fat as an energy reserve. AGPAT2 plays a key role in the synthesis of lipids, which are essential for various cellular functions.
What the gene does
The AGPAT2 enzyme is a crucial component of a biochemical pathway responsible for synthesising two important types of lipids: glycerophospholipids and triacylglycerols. Glycerophospholipids are vital constituents of cellular membranes and participate in intracellular signalling processes. Triacylglycerols, also known as triglycerides, are fat molecules primarily stored within adipocytes to be converted into energy when needed.
Specifically, the AGPAT2 enzyme facilitates a particular chemical reaction within this pathway. It catalyses the conversion of lysophosphatidic acid (LPA) into phosphatidic acid (PA). Subsequent reactions then transform phosphatidic acid into the final glycerophospholipids and triacylglycerols.
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Chromosome location
The AGPAT2 gene is situated on chromosome 9, specifically at position 9q34.3. This location refers to the long (q) arm of chromosome 9, within region 34 and sub-band 3. This genomic address precisely identifies where the AGPAT2 gene is found within the human genome.
Protein structure
The AGPAT2 protein is composed of 278 amino acids. It contains two characterised motifs essential for its function. These include the HXXXXD motif, located between amino acids 98 and 103, and the EGTR motif, found between amino acids 172 and 175. These motifs are thought to be important for the enzyme's catalytic activity.
Key variants
Genetic variations, or variants, in the AGPAT2 gene can alter the enzyme's structure or function, potentially impacting lipid metabolism and adipocyte development. These changes can range from single nucleotide substitutions to larger deletions or insertions within the gene sequence. The specific effect of a variant depends on its location and how it influences the production or activity of the AGPAT2 enzyme.
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 | ★★☆☆ | Congenital generalized lipodystrophy |
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
Pathogenic variants in the AGPAT2 gene are primarily associated with inherited disorders affecting fat tissue. The most notable condition linked to AGPAT2 variants is congenital lipodystrophy type 1. This rare disorder is characterised by a significant, often near-total, absence of adipose (fat) tissue from birth, leading to a distinctive highly muscular appearance and a range of metabolic complications.
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 recognised within the UK's National Health Service (NHS) Genomic Medicine Service. It is listed on several green-rated NHS Genomic Test Directory panels, indicating strong evidence for its involvement in specific conditions. These include the 'Diabetes with additional phenotypes suggestive of a monogenic aetiology', 'Familial diabetes', 'Insulin resistance (including lipodystrophy)', and 'Severe insulin resistance and lipodystrophy syndromes (R158)' panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the AGPAT2 gene responsible for?
The AGPAT2 gene provides instructions for an enzyme involved in synthesising two important types of fats: glycerophospholipids, which form cell membranes, and triacylglycerols, which are stored as energy in fat cells. It is crucial for the growth and development of adipocytes, the body's fat-storing cells.
What health conditions are associated with AGPAT2 variants?
Variants in the AGPAT2 gene are primarily linked to congenital lipodystrophy type 1, also known as Berardinelli-Seip congenital lipodystrophy type 1. This condition is characterised by a near-complete lack of fat tissue throughout the body from birth.
How does the AGPAT2 enzyme work?
The AGPAT2 enzyme performs a specific step in the production of fats, converting lysophosphatidic acid (LPA) into phosphatidic acid (PA). This phosphatidic acid is then further processed to create glycerophospholipids and triacylglycerols, which are essential for cell structure and energy storage.
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