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LIPA
lipase A, lysosomal acid type
The LIPA gene provides instructions for producing lysosomal acid lipase, an enzyme vital for breaking down fats within lysosomes. The LIPA gene encodes for lysosomal acid lipase, an enzyme that plays a crucial role in lipid metabolism by breaking down cholesteryl esters and triglycerides.
LIPA is located on the long (q) arm of chromosome 10, at band 10q23.31. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
The LIPA gene, also known as lipase A, lysosomal acid type, provides the genetic blueprint for an enzyme called lysosomal acid lipase. This enzyme is primarily located within lysosomes, which are cellular compartments responsible for digesting and recycling waste materials. Its primary function involves the breakdown and processing of specific fat molecules [PMID:17968853].
What the gene does
Lysosomal acid lipase, an enzyme generated from the LIPA gene, is crucial for lipid metabolism within cellular lysosomes. This enzyme works to dismantle complex fats, specifically cholesteryl esters and triglycerides. Cholesteryl esters are composed of cholesterol linked to a fatty acid, and the enzyme separates these components. Additionally, the enzyme processes triglycerides, which are stored fats, into fatty acids that can be utilised for energy [PMID:23783942]. The products resulting from these breakdown processes are either used by the body for various biological functions or transported to the liver for further processing and eventual removal.
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Chromosome location
The LIPA gene is situated on chromosome 10, specifically at position 10q23.31. This genomic location specifies its precise address within the human genome.
Protein structure
The LIPA protein, identified as lysosomal acid lipase, consists of 399 amino acids. It features a significant AB hydrolase-1 domain, spanning from amino acid positions 80 to 380, which is characteristic of enzymes involved in hydrolysing ester bonds [PMID:23783942].
Key variants
Genetic variations within the LIPA gene can alter the function or production of lysosomal acid lipase. These changes can range from single nucleotide substitutions to larger deletions or insertions, potentially affecting the enzyme's ability to break down lipids effectively.
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.1180_1184del | p.Leu394fs | Pathogenic/Likely pathogenic | ★★☆☆ | Wolman disease |
c.131G>A | p.Trp44Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Wolman disease |
c.132G>A | p.Trp44Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Wolman disease |
c.213del | p.Asn72fs | Pathogenic/Likely pathogenic | ★★☆☆ | Lysosomal acid lipase deficiency |
c.294C>A | p.Asn98Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Wolman disease |
c.331dup | p.Ala111fs | Pathogenic/Likely pathogenic | ★★☆☆ | Lysosomal acid lipase deficiency |
c.538+1G>A | - | Pathogenic | ★★☆☆ | Lysosomal acid lipase deficiency |
c.611_618del | p.Ala204fs | Pathogenic/Likely pathogenic | ★★☆☆ | Lysosomal acid lipase deficiency |
c.615_624del | p.Ala207fs | Pathogenic/Likely pathogenic | ★★☆☆ | Lysosomal acid lipase deficiency |
c.652C>T | p.Arg218Ter | Pathogenic | ★★☆☆ | Wolman disease |
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 LIPA gene are associated with a spectrum of conditions, including Wolman disease and Cholesterol Ester Storage Disease (CESD), collectively known as lysosomal acid lipase deficiency. These autosomal recessive conditions arise from insufficient functional lysosomal acid lipase, leading to the harmful accumulation of fats in various tissues and organs throughout the body.
- Wolman disease / CESD Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic LIPA 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 LIPA gene is an important focus for genetic testing within the UK, appearing on several NHS Genomic Medicine Service national panels. These include panels for Cholestasis (R171), Familial hypercholesterolaemia, Foetal anomalies (R21), Foetal hydrops, Likely inborn error of metabolism (R98), Lysosomal acid lipase deficiency (R325), Lysosomal storage disorder (R276), Neonatal cholestasis, and Undiagnosed metabolic disorders, indicating its relevance in diagnosing a range of inherited conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the LIPA gene?
The LIPA gene provides instructions for creating lysosomal acid lipase, an enzyme found in lysosomes. This enzyme is crucial for breaking down fats like cholesteryl esters and triglycerides into components the body can use or remove.
What happens if the LIPA gene doesn't work correctly?
If the LIPA gene is not functioning properly, it can lead to a deficiency of lysosomal acid lipase. This deficiency causes fats to accumulate in cells and tissues, resulting in conditions such as Wolman disease and Cholesterol Ester Storage Disease (CESD).
How is lysosomal acid lipase deficiency inherited?
Lysosomal acid lipase deficiency, caused by variants in the LIPA gene, is inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the gene, one from each parent, to develop the condition.
References
- Reiner Ž, Guardamagna O, Nair D. Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014. PMID: 24792990
- Zhang B, Porto AF. Cholesteryl ester storage disease: protean presentations of lysosomal acid lipase deficiency. Journal of pediatric gastroenterology and nutrition. 2013. PMID: 23403440
- Scott SA, Liu B, Nazarenko I. Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups. Hepatology (Baltimore, Md.). 2013. PMID: 23424026
- Saito S, Ohno K, Suzuki T. Structural bases of Wolman disease and cholesteryl ester storage disease. Molecular genetics and metabolism. 2012. PMID: 22138108