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LPL
lipoprotein lipase
The LPL gene provides instructions for creating lipoprotein lipase, an enzyme crucial for the breakdown of fats (triglycerides) transported in the bloodstream. The LPL gene is essential for lipid metabolism, encoding an enzyme that processes dietary fats and those synthesised by the liver.
LPL is located on the short (p) arm of chromosome 8, at band 8p21.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The LPL gene encodes the enzyme lipoprotein lipase, which plays a central role in the body's metabolism of fats. This enzyme is primarily found on the surface of cells lining tiny blood vessels within muscle and adipose (fat) tissues.
Its main function is to break down triglycerides, a type of fat molecule carried in the blood by lipoproteins. This process is vital for providing energy to tissues and for storing fat for future use.
What the gene does
Lipoprotein lipase, encoded by the LPL gene, is a key enzyme in the breakdown of triglycerides. These fats are transported in the bloodstream by two primary types of lipoproteins: chylomicrons, which carry dietary fat from the intestine, and very low-density lipoproteins (VLDLs), which transport triglycerides from the liver.
When lipoprotein lipase acts on these lipoproteins, it hydrolyses triglycerides into fatty acids and glycerol. These components can then be taken up by cells to be used as an energy source or converted back into triglycerides for storage in adipose tissue.
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Chromosome location
The LPL gene is located on chromosome 8, specifically at position 8p21.3. This gene spans approximately 30 kilobases and is composed of 10 exons. The precise location on the chromosome ensures its correct expression and function within the human genome.
Protein structure
The LPL protein consists of 475 amino acids and features several distinct functional regions. An interaction site with GPIHBP1 is located between amino acids 32 and 53, and another similar interaction region spans amino acids 443-467. The segment between amino acids 243 and 266 is essential for determining the enzyme's substrate specificity. A PLAT domain, located from amino acids 341 to 464, contributes to the protein's overall structure and function. Furthermore, a region between amino acids 417 and 421 is important for interaction with lipoprotein particles, while another region from amino acids 430 to 434 is crucial for heparin binding.
Key variants
Variations within the LPL gene can affect the enzyme's activity and efficiency in breaking down triglycerides. More than 220 different variants have been identified, including changes that replace specific amino acids. These genetic differences can lead to either reduced or, in some cases, increased lipoprotein lipase activity.
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.1014C>A | p.Tyr338Ter | Pathogenic | ★★☆☆ | Hyperlipoproteinemia, type I |
c.1019-2A>T | - | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1250G>A | p.Trp417Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperlipoproteinemia, type I |
c.3G>C | p.Met1Ile | Pathogenic | ★★☆☆ | Hyperlipoproteinemia, type I |
c.440_443del | p.Asn147fs | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.573T>G | p.Tyr191Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperlipoproteinemia, type I |
c.89-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperlipoproteinemia, type I |
c.89-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperlipoproteinemia, type I |
c.899_921dup | p.Asn308delinsGlySerAlaTer | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.984G>T | p.Met328Ile | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperlipidemia, familial combined, LPL related |
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 LPL gene are associated with inherited conditions primarily affecting lipid metabolism. The most well-known condition is familial chylomicronaemia syndrome, which is inherited in an autosomal recessive manner. This syndrome results from a significantly impaired ability to break down triglycerides, leading to their accumulation in the blood.
Inheritance pattern
Conditions caused by pathogenic LPL 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 LPL gene is included on several UK NHS national genomic testing panels. It is part of panels for Familial Chylomicronaemia Syndrome (R324), Likely inborn error of metabolism (R98), Severe hypertriglyceridaemia, and Undiagnosed metabolic disorders, indicating its clinical significance within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of the LPL gene?
The LPL gene provides instructions for making lipoprotein lipase, an enzyme that breaks down triglycerides (fats) in the bloodstream. This process is crucial for supplying energy to cells and for fat storage.
How do LPL gene variants affect health?
Variants in the LPL gene can impair the enzyme's ability to break down fats, leading to increased levels of triglycerides in the blood. This can result in conditions such as familial chylomicronaemia syndrome.
What is familial chylomicronaemia syndrome?
Familial chylomicronaemia syndrome is an inherited condition caused by genetic changes in the LPL gene. It leads to very high levels of triglycerides in the blood because the body cannot effectively process dietary fats.
References
- Pirim D, Wang X, Radwan ZH. Lipoprotein lipase gene sequencing and plasma lipid profile. Journal of lipid research. 2014. PMID: 24212298
- Kersten S. Physiological regulation of lipoprotein lipase. Biochimica et biophysica acta. 2014. PMID: 24721265
- Tang W, Apostol G, Schreiner PJ. Associations of lipoprotein lipase gene polymorphisms with longitudinal plasma lipid trends in young adults: The Coronary Artery Risk Development in Young Adults (CARDIA) study. Circulation. Cardiovascular genetics. 2010. PMID: 20150529
- Mead JR, Ramji DP. The pivotal role of lipoprotein lipase in atherosclerosis. Cardiovascular research. 2002. PMID: 12123765
- Mead JR, Irvine SA, Ramji DP. Lipoprotein lipase: structure, function, regulation, and role in disease. Journal of molecular medicine (Berlin, Germany). 2002. PMID: 12483461
- Gilbert B, Rouis M, Griglio S. Lipoprotein lipase (LPL) deficiency: a new patient homozygote for the preponderant mutation Gly188Glu in the human LPL gene and review of reported mutations: 75 % are clustered in exons 5 and 6. Annales de genetique. 2001. PMID: 11334614
- Benlian P, De Gennes JL, Foubert L. Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene. The New England journal of medicine. 1996. PMID: 8778602