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LAMP2
lysosome associated membrane protein 2
The *LAMP2* gene provides instructions for creating lysosome-associated membrane glycoprotein 2, a crucial protein involved in lysosome function and cellular waste management. The *LAMP2* gene plays a vital role in cellular health by encoding the LAMP-2 protein, which is integral to the membranes of lysosomes.
LAMP2 is located on the long (q) arm of chromosome X, at band Xq24. Arm ratio per GRCh38 - banding schematic.
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Overview
The *LAMP2* gene, also known as lysosome associated membrane protein 2, is essential for normal cellular function, particularly within the lysosomal system. This gene provides the blueprint for the LAMP-2 protein, which is critical for the proper operation of lysosomes-the cell's recycling centres. Understanding the *LAMP2* gene's role is important for comprehending conditions linked to lysosomal dysfunction.
The LAMP-2 protein helps facilitate the transport of cellular materials and digestive enzymes into lysosomes for degradation. Variations in the *LAMP2* gene can impact this crucial process, leading to the accumulation of waste products and cellular damage, particularly in tissues like the heart and skeletal muscles.
What the gene does
The *LAMP2* gene codes for the lysosome-associated membrane glycoprotein 2 (LAMP-2) protein, which is embedded in the lysosomal membrane. Lysosomes are cellular organelles responsible for the breakdown and recycling of waste products, old cell components, and foreign materials. The LAMP-2 protein is integral to these processes, assisting with the transport of substances into the lysosome for digestion.
Several versions, or isoforms, of the LAMP-2 protein exist, including LAMP-2A, LAMP-2B, and LAMP-2C, each with slightly different functions and tissue distributions. For example, LAMP-2A helps transport certain proteins for degradation, while LAMP-2B is crucial for the fusion of autophagic vacuoles with lysosomes, a key step in a process called autophagy, where cells 'self-eat' to remove damaged components. LAMP-2B is notably abundant in heart and skeletal muscle tissues. LAMP-2C assists in moving DNA and RNA building blocks into lysosomes for breakdown.
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Chromosome location
The *LAMP2* gene is situated on the long arm of the X chromosome at position Xq24. This chromosomal location means that the gene follows an X-linked inheritance pattern. The *LAMP2* gene contains the genetic instructions for a protein composed of 410 amino acids.
Protein structure
The LAMP-2 protein is a complex glycoprotein with distinct structural regions crucial for its function. It features a First lumenal domain, spanning amino acids 29-192, which projects into the lysosome's interior. Following this is a Hinge region, from amino acids 193-228, which includes a Disordered segment between amino acids 199-221, suggesting flexibility. A Second lumenal domain is found between amino acids 229-375. Crucially, a specific region from amino acids 401-404 is important for binding and subsequent lysosomal degradation of target proteins, highlighting its role in material recycling.
Key variants
Variants within the *LAMP2* gene can lead to changes in the structure or function of the LAMP-2 protein. These genetic alterations can disrupt the normal activity of lysosomes, affecting the cell's ability to clear waste and recycle cellular components effectively. Over a hundred different pathogenic variants in the *LAMP2* gene have been identified, each potentially impacting the protein's integrity or production levels.
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.1057C>T | p.Gln353Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Danon disease |
c.1075C>T | p.Gln359Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.183+2T>C | - | Pathogenic | ★★☆☆ | Danon disease |
c.190_191del | p.Val64fs | Pathogenic/Likely pathogenic | ★★☆☆ | LAMP2-related disorders |
c.1A>C | p.Met1Leu | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1A>T | p.Met1Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Danon disease |
c.631del | p.Thr211fs | Pathogenic | ★★☆☆ | Danon disease |
c.659dup | p.Gly221fs | Pathogenic/Likely pathogenic | ★★☆☆ | Danon disease |
c.696T>A | p.Cys232Ter | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.718C>T | p.Gln240Ter | Pathogenic | ★★☆☆ | LAMP2-related disorders |
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 *LAMP2* gene are primarily associated with Danon disease, an inherited condition characterised by a trio of symptoms: weakening of the heart muscle (cardiomyopathy), weakening of the skeletal muscles (myopathy), and intellectual disabilities. This condition typically manifests due to the production of little to no functional LAMP-2 protein, impairing lysosomal function. As the *LAMP2* gene is located on the X chromosome, Danon disease exhibits an X-linked inheritance pattern.
Inheritance pattern
Conditions caused by pathogenic LAMP2 variants typically follow X-linked inheritance.
Carrier frequency by population How common is heterozygous LAMP2 carrier status across ancestry groups?UK clinical status
The *LAMP2* gene is recognised within the NHS Genomic Medicine Service due to its clinical significance. It is included in several NHS England National Genomic Test Directory panels, indicating its importance in diagnosing a range of conditions. These include panels for Acute rhabdomyolysis, Dilated and arrhythmogenic cardiomyopathy, Glycogen storage disease, Hypertrophic cardiomyopathy, and Paediatric or syndromic cardiomyopathy, among others. Its inclusion signifies that testing for *LAMP2* variants is available where clinically appropriate within the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the LAMP-2 protein?
The LAMP-2 protein is primarily located in the membrane of lysosomes, where it facilitates the transport of cellular materials and digestive enzymes into these organelles for breakdown and recycling. This role is crucial for maintaining cellular health and waste management.
What is Danon disease?
Danon disease is a genetic disorder caused by variants in the *LAMP2* gene. It is characterised by cardiomyopathy (heart muscle weakness), myopathy (skeletal muscle weakness), and intellectual disability, resulting from insufficient functional LAMP-2 protein.
How is the *LAMP2* gene inherited?
The *LAMP2* gene is located on the X chromosome, meaning it follows an X-linked inheritance pattern. This typically means that males are more severely affected by associated conditions, as they have only one X chromosome.
References
- Malicdan MC, Noguchi S, Nonaka I. Lysosomal myopathies: an excessive build-up in autophagosomes is too much to handle. Neuromuscular disorders : NMD. 2008. PMID: 18502640
- Eskelinen EL. Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Molecular aspects of medicine. 2006. PMID: 16973206
- Arad M, Maron BJ, Gorham JM. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. The New England journal of medicine. 2005. PMID: 15673802
- Eskelinen EL, Illert AL, Tanaka Y. Role of LAMP-2 in lysosome biogenesis and autophagy. Molecular biology of the cell. 2002. PMID: 12221139
- Nishino I, Fu J, Tanji K. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 2000. PMID: 10972294
- Konecki DS, Foetisch K, Zimmer KP. An alternatively spliced form of the human lysosome-associated membrane protein-2 gene is expressed in a tissue-specific manner. Biochemical and biophysical research communications. 1995. PMID: 7488019