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LAMA2
laminin subunit alpha 2
The LAMA2 gene provides instructions for producing the alpha-2 subunit of laminin proteins, essential components of the extracellular matrix that are vital for maintaining skeletal muscle stability. The LAMA2 gene encodes the laminin subunit alpha 2 protein, which is a key part of laminin-211 (merosin) and laminin-221.
LAMA2 is located on the long (q) arm of chromosome 6, at band 6q22.33. Arm ratio per GRCh38 - banding schematic.
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Overview
The LAMA2 gene, also known as laminin subunit alpha 2, provides genetic instructions for the alpha-2 subunit, which is a component of several laminin proteins. These laminins are integral to the extracellular matrix, a complex network of proteins and other molecules that surrounds and supports cells [PMID:17006847].
Within the extracellular matrix, laminin proteins facilitate critical cellular processes including cell growth, movement, and adhesion. The LAMA2 gene is particularly important for the proper function of skeletal muscles, and pathogenic changes in this gene can lead to inherited conditions affecting muscle strength and function.
What the gene does
The LAMA2 gene directs the synthesis of the alpha-2 subunit, which is a crucial component of specific laminin proteins. For instance, it combines with the beta-1 and gamma-1 subunits to form laminin-211, also known as merosin [PMID:35467389]. Additionally, it forms laminin-221 with the beta-2 and gamma-1 subunits. These laminins are found in the extracellular matrix, which is the network of molecules that provides structural and biochemical support to surrounding cells.
Laminins are fundamental for cell adhesion, migration, and the organisation of basement membranes, which are specialised layers of the extracellular matrix that underpin and separate cells in many tissues. In skeletal muscles, laminin-211 and laminin-221 are especially important. They link to other proteins in the extracellular matrix and to muscle cell membranes, which is vital for preserving the structural integrity and stability of muscle fibres.
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Chromosome location
The LAMA2 gene is located on chromosome 6, specifically at position 6q22.33. This chromosomal region contains the genetic information necessary for producing the laminin subunit alpha 2 protein.
Protein structure
The LAMA2 gene encodes a large protein consisting of 3122 amino acids. This protein features several distinct domains that contribute to its overall structure and function. These include the Laminin N-terminal domain (amino acids 35-286), followed by multiple Laminin EGF-like domains such as Laminin EGF-like 1 (amino acids 287-343), Laminin EGF-like 2 (amino acids 344-413), Laminin EGF-like 3 (amino acids 414-468), Laminin EGF-like 4 (amino acids 469-517), Laminin EGF-like 5; first part (amino acids 518-527), Laminin EGF-like 5; second part (amino acids 724-756), Laminin EGF-like 6 (amino acids 757-806), Laminin EGF-like 7 (amino acids 807-864), Laminin EGF-like 8 (amino acids 865-917), Laminin EGF-like 9 (amino acids 918-966), Laminin EGF-like 10 (amino acids 967-1013), Laminin EGF-like 11 (amino acids 1014-1059), and Laminin EGF-like 12 (amino acids 1060-1105). A Laminin IV type A 1 domain is also present (amino acids 531-723).
Key variants
Variants within the LAMA2 gene can alter the structure or production of the laminin alpha-2 subunit. Over 100 different pathogenic variants have been identified in individuals with LAMA2-related conditions. These genetic changes can impair the protein's ability to support muscle fibres and interact with other extracellular matrix components, leading to a spectrum of clinical presentations.
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.1693C>T | p.Gln565Ter | Pathogenic | ★★☆☆ | LAMA2-related muscular dystrophy |
c.3768_3771dup | p.Tyr1258fs | Pathogenic | ★★☆☆ | LAMA2-related disorder |
c.6894dup | p.Phe2299fs | Pathogenic/Likely pathogenic | ★★☆☆ | Merosin deficient congenital muscular dystrophy |
c.7042dup | p.Tyr2348fs | Pathogenic/Likely pathogenic | ★★☆☆ | Merosin deficient congenital muscular dystrophy |
c.8380del | p.Arg2794fs | Pathogenic/Likely pathogenic | ★★☆☆ | LAMA2-related muscular dystrophy |
c.8703+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | LAMA2-related muscular dystrophy |
c.283+2T>C | - | Pathogenic | ★☆☆☆ | LAMA2-related muscular dystrophy |
c.4671T>A | p.Cys1557Ter | Pathogenic | ★☆☆☆ | LAMA2-related muscular dystrophy |
c.5779del | p.Ala1927fs | Pathogenic | ★☆☆☆ | LAMA2-related muscular dystrophy |
c.7271del | p.Ser2424fs | Pathogenic | ★☆☆☆ | Merosin deficient congenital muscular dystrophy |
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 LAMA2 gene are primarily associated with Merosin-deficient congenital muscular dystrophy (MDC1A), which is also known as LAMA2-related muscular dystrophy. This condition typically presents with muscle weakness and wasting, with severity ranging from severe early-onset forms to milder presentations later in life [PMID:10729221]. Individuals with severe forms often have a complete absence of the alpha-2 subunit, while those with milder forms may have reduced levels.
Inheritance pattern
Conditions caused by pathogenic LAMA2 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 LAMA2 gene is included on several NHS Genomic Medicine Service national panels, indicating its recognised clinical importance within the UK healthcare system. These panels include those for Arthrogryposis, Congenital muscular dystrophy (R79), DDG2P, Foetal anomalies (R21), Intellectual disability, and Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies (R82). This inclusion supports genetic testing for individuals with suspected related conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the LAMA2 gene?
The LAMA2 gene provides instructions for making the alpha-2 subunit of laminin proteins, such as laminin-211. These proteins are crucial components of the extracellular matrix and are essential for maintaining the stability and integrity of skeletal muscle fibres.
What conditions are associated with LAMA2 gene variants?
Pathogenic variants in the LAMA2 gene are primarily associated with Merosin-deficient congenital muscular dystrophy (MDC1A), also known as LAMA2-related muscular dystrophy. This condition causes progressive muscle weakness and wasting.
How common are LAMA2-related muscular dystrophies?
LAMA2-related muscular dystrophies are considered rare genetic conditions. The exact prevalence can vary by population, but they are among the most common forms of congenital muscular dystrophy [PMID:20301323].
References
- Gavassini BF, Carboni N, Nielsen JE. Clinical and molecular characterization of limb-girdle muscular dystrophy due to LAMA2 mutations. Muscle & nerve. 2011. PMID: 21953594
- Geranmayeh F, Clement E, Feng LH. Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations. Neuromuscular disorders : NMD. 2010. PMID: 20207543
- Allamand V, Guicheney P. Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225, LAMA2 gene coding for alpha2 chain of laminin). European journal of human genetics : EJHG. 2002. PMID: 11938437
- Jones KJ, Morgan G, Johnston H. The expanding phenotype of laminin alpha2 chain (merosin) abnormalities: case series and review. Journal of medical genetics. 2001. PMID: 11584042
- Miyagoe-Suzuki Y, Nakagawa M, Takeda S. Merosin and congenital muscular dystrophy. Microscopy research and technique. 2000. PMID: 10679965