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LPL
lipoprotein lipase
The LPL gene provides instructions for producing lipoprotein lipase, an enzyme critical for breaking down fats (triglycerides) in the bloodstream, enabling their use for energy or storage. The LPL gene is essential for proper lipid metabolism, as it directs the synthesis of lipoprotein lipase.
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, or lipoprotein lipase, plays a pivotal role in the body's fat metabolism. It provides the genetic blueprint for creating the lipoprotein lipase enzyme, which is primarily located on the surface of capillary cells within muscles and adipose (fatty) tissues. This enzyme is crucial for processing dietary fats and fats produced by the liver, ensuring that the body has access to energy and can store excess lipids efficiently.
Disruptions in the normal function of the LPL gene can lead to altered triglyceride levels in the blood, potentially contributing to various health issues related to lipid processing.
What the gene does
The lipoprotein lipase enzyme, encoded by the LPL gene, is a key component in the breakdown of triglycerides. Triglycerides are a type of fat transported in the blood by lipoprotein particles, specifically chylomicrons (from dietary intake via the intestine) and very low-density lipoproteins (VLDLs, from the liver). Lipoprotein lipase acts to hydrolyse these triglycerides into free fatty acids and glycerol.
Once released, these fatty acids can either be taken up by muscle cells for immediate energy use or by adipose cells for storage. The efficient functioning of this enzyme is therefore vital for maintaining healthy fat levels in the blood and ensuring that the body can properly utilise and store fats.
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Chromosome location
The LPL gene is situated on chromosome 8, specifically at position 8p21.3. This genomic location dictates where the gene is found within the human genome and is consistent across individuals.
Protein structure
The LPL protein is composed of 475 amino acids and contains several functional regions important for its enzymatic activity and interactions. A region spanning amino acids 32-53 is involved in interaction with GPIHBP1. Amino acids 243-266 are essential for determining the enzyme's substrate specificity. The protein also features a PLAT domain from amino acids 341-464. Furthermore, specific regions are important for interaction with lipoprotein particles (amino acids 417-421), heparin binding (amino acids 430-434), and another interaction with GPIHBP1 (amino acids 443-467).
Key variants
Over 220 different genetic variations, often called mutations, have been identified within the LPL gene. These variations can lead to changes in the lipoprotein lipase enzyme, affecting its ability to break down triglycerides. The impact of a variant can range from subtle alterations in enzyme activity to a complete loss of function, influencing an individual's lipid profile and overall health.
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.1014C>G | p.Tyr338Ter | Pathogenic/Likely pathogenic | ★★☆☆ | LPL-related disorder |
c.1019-2A>T | - | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1250G>A | p.Trp417Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperlipoproteinemia, type I |
c.250-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | LPL-related disorder |
c.3G>C | p.Met1Ile | Pathogenic | ★★☆☆ | Hyperlipoproteinemia, type I |
c.440_443del | p.Asn147fs | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.557G>A | p.Gly186Glu | Pathogenic/Likely pathogenic | ★★☆☆ | LPL-related disorder |
c.573T>G | p.Tyr191Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperlipoproteinemia, type I |
c.655C>T | p.Arg219Ter | Pathogenic | ★★☆☆ | LPL-related disorder |
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
Variations in the LPL gene are primarily associated with conditions affecting lipid metabolism. The most well-known condition is Familial chylomicronaemia syndrome, which is inherited in an autosomal recessive pattern. This syndrome results from a significant impairment in triglyceride breakdown, leading to very high levels of chylomicrons and triglycerides in the blood. Other LPL variants can influence blood fat levels, sometimes leading to increased or decreased triglyceride concentrations, potentially contributing to conditions like severe hypertriglyceridaemia.
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
In the UK, the LPL gene is included on several NHS Genomic Medicine Service approved panels. These include panels for Familial Chylomicronaemia Syndrome, Likely inborn error of metabolism, Severe hypertriglyceridaemia, and Undiagnosed metabolic disorders, indicating its clinical relevance in diagnosing and managing these conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the LPL gene?
The LPL gene provides instructions for making lipoprotein lipase, an enzyme that breaks down triglycerides in the bloodstream. This process is crucial for converting fats into energy or for storage in the body.
What happens if the LPL gene does not function correctly?
If the LPL gene does not function correctly, the breakdown of triglycerides can be impaired. This can lead to an accumulation of fats in the blood, potentially causing conditions such as familial chylomicronaemia syndrome or severe hypertriglyceridaemia.
How is Familial chylomicronaemia syndrome inherited?
Familial chylomicronaemia syndrome is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic LPL gene variant (one from each parent) to develop the condition.
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