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LAMA3
laminin subunit alpha 3
The LAMA3 gene provides instructions for a key component of laminin 332, a protein vital for skin structure and integrity, and is associated with certain inherited skin disorders. LAMA3 encodes the alpha-3 subunit of laminin 332, a critical protein found in the basement membranes that support skin and other tissues.
LAMA3 is located on the long (q) arm of chromosome 18, at band 18q11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The LAMA3 gene is responsible for producing the alpha-3 subunit of laminin 332, a complex protein essential for maintaining the structure and resilience of various tissues in the body, particularly the skin. Laminins are a family of proteins that play a crucial role in cell adhesion, growth, and movement, and are fundamental components of basement membranes.
Disruptions to LAMA3 function can lead to inherited conditions characterised by fragile skin and blistering, underscoring its importance in epidermal integrity.
What the gene does
LAMA3 provides the genetic blueprint for one of three subunits (alpha, beta, gamma) that assemble to form laminin 332, previously known as laminin 5. Specifically, LAMA3 directs the synthesis of the alpha-3 subunit, which can exist in multiple forms (alpha-3a, alpha-3b1, alpha-3b2). This laminin is a major constituent of basement membranes, which are thin, supportive layers separating and anchoring cells in many tissues.
Laminin 332 is particularly vital for the dermal-epidermal junction, providing strength to the skin and forming a protective barrier. It is a key component of anchoring filaments, which physically connect the epidermal and dermal layers. Beyond its structural role in skin, laminin 332 is also implicated in wound healing, corneal function, and the development of tooth enamel. The alpha-3 subunit also contributes to other laminin proteins, laminin 311 and laminin 321, which offer additional structural support to the skin and are involved in cell signalling.
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Chromosome location
The LAMA3 gene is situated on chromosome 18, specifically at position 18q11.2. This genomic location specifies the precise band on the long arm of chromosome 18 where the gene can be found.
Protein structure
The LAMA3 gene encodes a protein that is 3333 amino acids in length. This protein features several distinct domains that contribute to its overall function. Key regions include the Laminin N-terminal domain (amino acids 43-298), followed by Domain V (amino acids 298-728), which contains multiple Laminin EGF-like domains (Laminin EGF-like 1, 2, 3, 4, 5, 6, 7, and 8). Further along the protein are Domain IV 1 (domain IV B) (amino acids 796-1265) and Domain III B (amino acids 1266-1465), which incorporates additional Laminin EGF-like domains (Laminin EGF-like 9, 10, and 11).
Key variants
Variants within the LAMA3 gene can alter the production or function of the alpha-3 subunit, thereby affecting the assembly and stability of laminin 332. These genetic changes can range from single nucleotide changes to larger deletions or insertions, impacting the protein's ability to maintain tissue integrity. The clinical consequences of these variants depend on their specific effect on protein function.
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.1273+51C>T | R442* | Pathogenic/Likely pathogenic | ★★☆☆ | Laryngo-onycho-cutaneous syndrome |
c.5061C>A | p.Cys1687Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.5119C>T | p.Gln1707Ter | Pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 2B, severe |
c.7120C>T | p.Arg2374Ter | Pathogenic | ★★☆☆ | not provided |
c.7204C>T | p.Arg2402Ter | Pathogenic | ★★☆☆ | Laryngo-onycho-cutaneous syndrome |
c.8043G>A | p.Ser2681= | Pathogenic/Likely pathogenic | ★★☆☆ | Laryngo-onycho-cutaneous syndrome |
c.8211C>A | p.Cys2737Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 2B, severe |
c.8420T>G | p.Leu2807Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 2A, intermediate |
c.8705del | p.Gln2902fs | Pathogenic/Likely pathogenic | ★★☆☆ | Epidermolysis bullosa, junctional 2A, intermediate |
c.8755A>T | p.Lys2919Ter | 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 LAMA3 gene are primarily associated with inherited disorders affecting skin integrity, most notably Epidermolysis bullosa (junctional). This condition is characterised by extreme skin fragility and blistering due to impaired adhesion between the epidermal and dermal layers. Variants can also lead to Laryngo-onycho-cutaneous syndrome, which involves chronic skin ulcers and excessive granulation tissue formation.
Inheritance pattern
Conditions caused by pathogenic LAMA3 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
LAMA3 is recognised in the UK's NHS Genomic Medicine Service. It is currently listed on PanelApp UK for its association with Epidermolysis bullosa, including Epidermolysis bullosa and congenital skin fragility (R164), and Amelogenesis imperfecta (R340), indicating its clinical relevance for diagnostic testing within these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the LAMA3 gene?
The LAMA3 gene provides instructions for making the alpha-3 subunit of laminin 332, a protein crucial for maintaining the structural integrity and adhesion of skin and other tissues by forming part of their basement membranes.
What conditions are associated with LAMA3 gene variants?
Variants in the LAMA3 gene are primarily associated with inherited skin fragility disorders such as Epidermolysis bullosa (junctional) and Laryngo-onycho-cutaneous syndrome, which cause blistering and impaired tissue adhesion.
How does LAMA3 relate to laminin proteins?
LAMA3 encodes the alpha-3 subunit, which is a key component of laminin 332. This alpha-3 subunit also contributes to the formation of other laminin proteins like laminin 311 and laminin 321, all of which play roles in tissue structure and function.
References
- Barzegar M, Mozafari N, Kariminejad A. A new homozygous nonsense mutation in LAMA3A underlying laryngo-onycho-cutaneous syndrome. The British journal of dermatology. 2013. PMID: 23869449
- Hamill KJ, Paller AS, Jones JC. Adhesion and migration, the diverse functions of the laminin alpha3 subunit. Dermatologic clinics. 2010. PMID: 19945619
- 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
- Kim CC, Liang MG, Pfendner E. What syndrome is this? Laryngo-onycho-cutaneous syndrome. Pediatric dermatology. 2007. PMID: 17542886
- Varki R, Sadowski S, Pfendner E. Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. Journal of medical genetics. 2006. PMID: 16473856
- Hamill KJ, McLean WH. The alpha-3 polypeptide chain of laminin 5: insight into wound healing responses from the study of genodermatoses. Clinical and experimental dermatology. 2005. PMID: 15953081
- Aumailley M, Bruckner-Tuderman L, Carter WG. A simplified laminin nomenclature. Matrix biology : journal of the International Society for Matrix Biology. 2005. PMID: 15979864
- McLean WH, Irvine AD, Hamill KJ. An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome. Human molecular genetics. 2003. PMID: 12915477
- 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