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LAMP2
lysosome associated membrane protein 2
The *LAMP2* gene provides instructions for creating lysosome-associated membrane protein 2, which is critical for the proper functioning of lysosomes in cellular waste management. The *LAMP2* gene plays a vital role in cellular health by encoding a protein essential for lysosomal activity.
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 crucial for cellular function, particularly in processes involving lysosomes. Lysosomes are organelles within cells that act as the cell's recycling and waste disposal units, breaking down unwanted materials into their basic components for reuse or elimination. The protein produced from the *LAMP2* gene is integral to this process, facilitating the transport of substances into the lysosome for digestion.
What the gene does
The *LAMP2* gene directs the production of lysosome-associated membrane glycoprotein 2 (LAMP-2), a protein situated in the membrane of lysosomes. This protein is fundamental for transporting cellular materials and digestive enzymes into lysosomes. Different versions, or isoforms, of the LAMP-2 protein exist, specifically LAMP-2A, LAMP-2B, and LAMP-2C, each having distinct functions and tissue distributions. For instance, LAMP-2A aids in moving certain proteins into the lysosome for degradation, while LAMP-2B is essential for the fusion of autophagic vacuoles with lysosomes, a critical step in autophagy where cellular debris is recycled. LAMP-2B is notably prevalent in cardiac and skeletal muscles. LAMP-2C, on the other hand, facilitates the transport of DNA and RNA building blocks into lysosomes for breakdown.
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Chromosome location
The *LAMP2* gene is located on the long arm of the X chromosome at position 24, denoted as Xq24. This chromosomal location indicates its position within the human genome.
Protein structure
The LAMP-2 protein is composed of 410 amino acids. Key structural features include a First lumenal domain spanning amino acids 29-192, and a Second lumenal domain from amino acids 229-375. A Hinge region is found between amino acids 193-228, with a Disordered segment identified within this hinge region from amino acids 199-221. A critical region for binding and subsequent lysosomal degradation of target proteins is located at amino acids 401-404.
Key variants
Variants within the *LAMP2* gene can disrupt the normal production or function of the LAMP-2 protein. Such genetic changes may lead to a reduced amount of functional protein or an entirely non-functional protein, impairing the cell's ability to properly manage waste and recycle materials. These disruptions are associated with specific inherited conditions.
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.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 | ★★☆☆ | Danon disease |
c.929-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.974del | p.Leu325fs | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
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 recognised as the cause of Danon disease. Over one hundred distinct variants in the *LAMP2* gene have been identified as contributors to this condition. These genetic changes can lead to a deficiency or complete absence of the LAMP-2 protein, which impairs the cellular waste disposal system, particularly affecting muscle cells and neurons [PMID:16545199]. Danon disease is characterised by a constellation of symptoms including weakening of the heart muscle (cardiomyopathy), skeletal muscle weakness (myopathy), and intellectual disabilities [PMID:19398717]. The inheritance pattern for conditions linked to *LAMP2* is X-linked.
Inheritance pattern
Conditions caused by pathogenic LAMP2 variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
In the UK, the *LAMP2* gene is included on several NHS Genomic Medicine Service clinical panels, indicating its importance in diagnostic testing for specific conditions. These panels include: Acute rhabdomyolysis (R419), DDG2P, Dilated and arrhythmogenic cardiomyopathy (R132), Glycogen storage disease (R274), Hypertrophic cardiomyopathy (R131), Intellectual disability, Likely inborn error of metabolism (R98), Limb girdle muscular dystrophies/myofibrillar myopathies and distal myopathies (R82), Lysosomal storage disorder (R276), Paediatric or syndromic cardiomyopathy (R135), Progressive cardiac conduction disease (R328), Retinal disorders (R32), Rhabdomyolysis and metabolic muscle disorders, Undiagnosed metabolic disorders, and Vici Syndrome and other autophagy disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the LAMP2 gene?
The *LAMP2* gene provides instructions for making the LAMP-2 protein, which is essential for transporting materials into lysosomes, the cell's recycling centres, for digestion and breakdown.
Which condition is associated with variants in the LAMP2 gene?
Variants in the *LAMP2* gene are primarily associated with Danon disease, a condition affecting the heart, skeletal muscles, and cognitive function.
How is Danon disease inherited?
Danon disease is inherited in an X-linked recessive pattern. This means the gene responsible is located on the X chromosome. Typically, males are more severely affected because they have only one X chromosome, so a single altered copy of the gene is sufficient to cause the condition. Females have two X chromosomes; if one carries a variant, the other X chromosome may compensate, often leading to milder symptoms or making them carriers without significant health issues themselves.
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