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LAMB3
laminin subunit beta 3
The LAMB3 gene provides instructions for the beta-3 subunit of laminin 332, a critical protein for maintaining the structural integrity of skin and other tissues. LAMB3 is vital for forming laminin 332, a protein found in basement membranes that support and separate cells.
LAMB3 is located on the long (q) arm of chromosome 1, at band 1q32.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The LAMB3 gene encodes a component of laminin 332, a protein essential for the structure and function of basement membranes in various tissues, particularly the skin. These membranes provide support and act as a barrier between different cell layers. Understanding LAMB3's role is crucial for comprehending inherited conditions affecting tissue integrity, such as those causing skin fragility.
What the gene does
The LAMB3 gene provides instructions for the beta-3 subunit, which is one of three subunits (alpha, beta, and gamma) that form the protein laminin 332. Laminins are a family of proteins that regulate cell growth, movement, and adhesion, playing a key role in the formation and organisation of basement membranes. Laminin 332 is particularly important in the basement membrane underlying the epidermis, the outer layer of the skin. It contributes to the skin's strength and elasticity by forming anchoring filaments that connect skin layers. Beyond its structural role, laminin 332 also appears to be involved in wound healing and may have functions in the cornea of the eye and the development of tooth enamel.
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Chromosome location
The LAMB3 gene is situated on chromosome 1 at position 1q32.2. This genomic location specifies its precise address within the human genome. The gene spans a significant region on this chromosome, contributing to the broader genetic landscape.
Protein structure
The LAMB3 gene encodes a protein that is 1172 amino acids long. Its complex structure includes several distinct domains. These include a Laminin N-terminal domain (amino acids 22-249) and multiple Laminin EGF-like domains, specifically Laminin EGF-like 1 (amino acids 250-315), Laminin EGF-like 2 (amino acids 316-378), Laminin EGF-like 3 (amino acids 379-430), Laminin EGF-like 4 (amino acids 431-480), Laminin EGF-like 5 (amino acids 481-533), and Laminin EGF-like 6 (amino acids 534-580). Additionally, the protein contains Domain II (amino acids 579-785), Domain alpha (amino acids 786-816), and Domain I (amino acids 817-1170). Several coiled-coil regions are also present, located at amino acids 723-757, 831-884, and 948-1133.
Key variants
Variants in the LAMB3 gene can affect the production or function of the laminin 332 beta-3 subunit. These genetic changes can range from single nucleotide alterations to larger deletions or insertions within the gene sequence. The impact of a specific variant depends on its location and the type of change it introduces, potentially leading to a non-functional or absent 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.1357del | p.Cys453fs | Pathogenic/Likely pathogenic | ★★☆☆ | Junctional epidermolysis bullosa gravis of Herlitz |
c.1628dup | p.Cys546fs | Pathogenic | ★★☆☆ | Junctional epidermolysis bullosa, non-Herlitz type |
c.2116del | p.Lys705_Ile706insTer | Pathogenic | ★★☆☆ | Junctional epidermolysis bullosa gravis of Herlitz |
c.2242G>T | p.Glu748Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Amelogenesis imperfecta type 1A |
c.2269G>T | p.Gly757Ter | Pathogenic | ★★☆☆ | Junctional epidermolysis bullosa |
c.2495del | p.Ala832fs | Pathogenic/Likely pathogenic | ★★☆☆ | Amelogenesis imperfecta type 1A |
c.2911_2938del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Junctional epidermolysis bullosa gravis of Herlitz |
c.3163del | p.Ala1055fs | Pathogenic/Likely pathogenic | ★★☆☆ | Junctional epidermolysis bullosa gravis of Herlitz |
c.3190_3191delinsTA | p.Ala1064Ter | Pathogenic | ★★☆☆ | Junctional epidermolysis bullosa, non-Herlitz type |
c.877T>A | p.Cys293Ser | Pathogenic/Likely 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 LAMB3 gene are primarily associated with inherited conditions affecting skin integrity. The most notable of these is Epidermolysis bullosa (junctional), a group of rare genetic disorders characterised by extreme skin fragility and recurrent blistering. These conditions typically follow an autosomal recessive inheritance pattern, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to be affected. LAMB3 variants are also implicated in Amelogenesis imperfecta, a condition affecting tooth enamel development.
Inheritance pattern
Conditions caused by pathogenic LAMB3 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 LAMB3 gene is recognised within the UK's genomic healthcare system, as evidenced by its inclusion in several NHS Genomic Medicine Service national test directories. It is listed as 'green' for Epidermolysis bullosa, meaning there is strong evidence for its association with the condition and it is routinely investigated. It is also listed as 'green' for Amelogenesis imperfecta (R340) and Epidermolysis bullosa and congenital skin fragility (R164), indicating its established clinical utility in these areas.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the LAMB3 gene?
The LAMB3 gene provides instructions for making the beta-3 subunit of laminin 332, a crucial protein that helps form and maintain basement membranes. These membranes are essential for supporting cells and ensuring the structural integrity of tissues, especially the skin.
Which conditions are associated with LAMB3 gene variants?
Pathogenic variants in the LAMB3 gene are primarily associated with Epidermolysis bullosa (junctional), a group of inherited disorders causing severe skin blistering and fragility. It is also implicated in Amelogenesis imperfecta, which affects tooth enamel formation.
How is Epidermolysis bullosa (junctional) inherited?
Epidermolysis bullosa (junctional) caused by LAMB3 variants is inherited in an autosomal recessive manner. This means an individual must inherit two pathogenic copies of the gene, one from each parent, to develop the condition. Carriers, with only one pathogenic copy, typically do not show symptoms.
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
- Nakano A, Pfendner E, Hashimoto I. Herlitz junctional epidermolysis bullosa: novel and recurrent mutations in the LAMB3 gene and the population carrier frequency. The Journal of investigative dermatology. 2000. PMID: 11023379
- 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
- Pulkkinen L, Gerecke DR, Christiano AM. Cloning of the beta 3 chain gene (LAMB3) of human laminin 5, a candidate gene in junctional epidermolysis bullosa. Genomics. 1995. PMID: 7774918