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LAMC2
laminin subunit gamma 2
The LAMC2 gene provides instructions for making a critical component of laminin 332, a protein essential for the structural integrity and adhesion of skin and other tissues. The LAMC2 gene codes for the gamma-2 subunit of laminin 332, a key protein involved in cell adhesion and the formation of basement membranes.
LAMC2 is located on the long (q) arm of chromosome 1, at band 1q25.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The LAMC2 gene provides the genetic blueprint for the gamma-2 subunit of laminin 332, a complex protein formerly known as laminin 5. Laminin 332 plays a fundamental role in maintaining tissue structure, especially within the skin. This gene's proper function is vital for robust cellular attachment and overall tissue integrity.
What the gene does
Laminin 332 is a heterotrimeric protein composed of alpha, beta, and gamma subunits; the LAMC2 gene specifically instructs the cell to produce the gamma-2 subunit. Laminins are a family of proteins that regulate various cellular processes, including growth, motility, and adhesion. They are integral to the formation and organisation of basement membranes, which are thin, sheet-like structures that provide support and separation for cells in numerous tissues. Laminin 332 is particularly concentrated in the basement membrane beneath the epidermis, the top layer of skin. Here, it contributes significantly to the skin's strength and resilience, forming anchoring filaments that connect the two layers of the basement membrane and hold the skin together. Beyond skin, research indicates laminin 332 is important for wound healing, corneal structure, and tooth enamel development.
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Chromosome location
The LAMC2 gene is located on chromosome 1, specifically at position 1q25.3. This genomic address indicates its precise position on the long arm of chromosome 1. The gene spans a region of DNA that directs the synthesis of the 1193 amino acid-long laminin gamma 2 protein.
Protein structure
The LAMC2 gene codes for a protein 1193 amino acids in length. Its structure includes multiple Laminin EGF-like domains: Laminin EGF-like 1 (amino acids 28-83), Laminin EGF-like 2 (amino acids 84-130), Laminin EGF-like 3 (amino acids 139-186), Laminin EGF-like 4 (amino acids 187-196 and 382-415), Laminin EGF-like 5 (amino acids 416-461), Laminin EGF-like 6 (amino acids 462-516), Laminin EGF-like 7 (amino acids 517-572), and a truncated Laminin EGF-like 8 (amino acids 573-602). Additionally, the protein contains a Laminin IV type A domain (amino acids 213-381). A large Domain II and I region spans amino acids 603-1193, which includes three distinct coiled-coil regions (amino acids 611-718, 811-1076, and 1117-1193).
Key variants
Variants within the LAMC2 gene can alter the protein's structure or function, impacting its ability to form stable basement membranes. Over 40 different types of genetic variants have been identified in individuals with associated conditions. These variants can include changes that lead to a premature stop signal in the gene's instructions, often resulting in a non-functional or truncated protein.
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.1045C>T | p.Arg349Ter | Pathogenic | ★★☆☆ | Junctional epidermolysis bullosa |
c.1175del | p.Phe392fs | Pathogenic | ★★☆☆ | Junctional epidermolysis bullosa |
c.1211C>G | p.Ser404Ter | Pathogenic/Likely pathogenic | ★★☆☆ | LAMC2-related disorder |
c.1350C>A | p.Tyr450Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.136C>T | p.Gln46Ter | Pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 3B, severe |
c.1756C>T | p.Arg586Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 3A, intermediate |
c.1843C>T | p.Gln615Ter | Pathogenic | ★★☆☆ | Junctional epidermolysis bullosa |
c.1924G>T | p.Gly642Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 3A, intermediate |
c.2074C>T | p.Gln692Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Junctional epidermolysis bullosa |
c.2208del | p.Leu737fs | Pathogenic | ★★☆☆ | Junctional epidermolysis bullosa |
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 LAMC2 gene are inherited in an autosomal recessive pattern and are primarily associated with Epidermolysis bullosa (junctional). This group of inherited blistering skin disorders causes extreme skin fragility, where even minor trauma can lead to severe blistering and open wounds. The more severe forms of the condition, such as junctional epidermolysis bullosa generalised severe, typically arise from variants that completely prevent the production of functional laminin 332.
Inheritance pattern
Conditions caused by pathogenic LAMC2 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 LAMC2 gene is included in several UK NHS national genomic testing panels. It is listed as 'green' on the Epidermolysis bullosa panel and also on the Epidermolysis bullosa and congenital skin fragility panel (R164), indicating that there is strong evidence for its association with these conditions and that testing is routinely offered in the UK for diagnostic purposes.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the LAMC2 gene?
The LAMC2 gene provides instructions for the gamma-2 subunit of laminin 332, a protein vital for cell adhesion and the structural integrity of basement membranes, particularly in the skin. It helps to connect different layers of skin, providing strength and resilience.
How are conditions related to LAMC2 inherited?
Conditions associated with the LAMC2 gene, such as Epidermolysis bullosa (junctional), are inherited in an autosomal recessive manner. This means an individual must inherit two copies of a pathogenic variant, one from each parent, to develop the condition.
What happens if the LAMC2 gene does not function correctly?
If the LAMC2 gene does not function correctly, it can lead to impaired production or function of laminin 332. This can weaken the connections within the skin's basement membrane, causing extreme skin fragility and blistering, as seen in junctional epidermolysis bullosa.
References
- Schneider H, Mühle C, Pacho F. Biological function of laminin-5 and pathogenic impact of its deficiency. European journal of cell biology. 2007. PMID: 17000025
- Hartwig B, Borm B, Schneider H. Laminin-5-deficient human keratinocytes: defective adhesion results in a saltatory and inefficient mode of migration. Experimental cell research. 2007. PMID: 17335805
- Varki R, Sadowski S, Pfendner E. Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. Journal of medical genetics. 2006. PMID: 16473856
- Mühle C, Jiang QJ, Charlesworth A. Novel and recurrent mutations in the laminin-5 genes causing lethal junctional epidermolysis bullosa: molecular basis and clinical course of Herlitz disease. Human genetics. 2005. PMID: 15538630
- Aumailley M, Bruckner-Tuderman L, Carter WG. A simplified laminin nomenclature. Matrix biology : journal of the International Society for Matrix Biology. 2005. PMID: 15979864
- Nakano A, Chao SC, Pulkkinen L. Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-Herlitz phenotypes. Human genetics. 2002. PMID: 11810295
- Castiglia D, Posteraro P, Spirito F. Novel mutations in the LAMC2 gene in non-Herlitz junctional epidermolysis bullosa: effects on laminin-5 assembly, secretion, and deposition. The Journal of investigative dermatology. 2001. PMID: 11564184
- Pulkkinen L, Uitto J. Mutation analysis and molecular genetics of epidermolysis bullosa. Matrix biology : journal of the International Society for Matrix Biology. 1999. PMID: 10367729