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LAMA2
laminin subunit alpha 2
The LAMA2 gene encodes a subunit of laminin proteins, crucial for maintaining muscle fibre stability and overall tissue structure. LAMA2 provides instructions for the alpha-2 subunit of laminin proteins, specifically 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, or laminin subunit alpha 2, plays a vital role in human health by providing the genetic blueprint for a crucial component of laminin proteins. These proteins are fundamental to the extracellular matrix, a complex network of molecules that provides structural support and biochemical signalling to cells. Specifically, LAMA2 contributes to the formation of laminin-211 (also known as merosin) and laminin-221, which are particularly important in skeletal muscles.
Pathogenic variants in LAMA2 are associated with a spectrum of conditions, most notably LAMA2-related muscular dystrophy, which can manifest with varying severity from early to late onset. Understanding the function of LAMA2 is key to comprehending the biological basis of these muscle-related disorders.
What the gene does
The LAMA2 gene directs the synthesis of the alpha-2 subunit, which combines with beta-1 and gamma-1 subunits to form laminin-211 (merosin), or with beta-2 and gamma-1 subunits to form laminin-221. These laminin proteins are critical constituents of the extracellular matrix, the intricate network surrounding cells [PMID:17963246]. Within this matrix, laminins are involved in regulating essential cellular processes, including cell growth, movement, and adhesion.
Laminins are also instrumental in the organisation and formation of basement membranes. These thin, sheet-like structures within the extracellular matrix act as supportive barriers for cells in many tissues. In skeletal muscles, laminin-211 and laminin-221 have a particularly significant role. They facilitate the attachment of muscle cells to other proteins within the extracellular matrix, which is vital for maintaining the structural integrity and stability of muscle fibres [PMID:17963246].
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Chromosome location
The LAMA2 gene is situated on chromosome 6, specifically at band 6q22.33. This chromosomal location defines where the gene resides within the human genome. The LAMA2 gene is categorised as an autosomal recessive gene, meaning that typically two altered copies of the gene are required for an individual to develop an associated condition.
Protein structure
The LAMA2 protein, spanning 3122 amino acids, features a complex architecture crucial for its biological role. It contains a Laminin N-terminal domain (amino acids 35-286), followed by a series of 15 Laminin EGF-like domains. These include EGF-like 1 (287-343), EGF-like 2 (344-413), EGF-like 3 (414-468), EGF-like 4 (469-517), the first part of EGF-like 5 (518-527), EGF-like 6 (757-806), EGF-like 7 (807-864), EGF-like 8 (865-917), EGF-like 9 (918-966), EGF-like 10 (967-1013), EGF-like 11 (1014-1059), EGF-like 12 (1060-1105), EGF-like 13 (1106-1165), and two parts of EGF-like 14 (1166-1175 and 1380-1419), concluding with EGF-like 15 (1420-1468). Additionally, the protein incorporates two Laminin IV type A domains: one at amino acids 531-723 and another at amino acids 1176-1379, along with the second part of Laminin EGF-like 5 (724-756).
Key variants
Variants within the LAMA2 gene can lead to alterations in the alpha-2 laminin subunit, which can impair the formation and function of laminin proteins. These genetic changes can range from small point mutations to larger deletions or insertions, all of which may disrupt the gene's ability to produce a functional protein. Over 100 different variants have been identified in individuals with LAMA2-related muscular dystrophy, affecting the stability and integrity of muscle fibres [PMID:10091176].
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.2413C>T | p.Gln805Ter | Pathogenic | ★☆☆☆ | LAMA2-related muscular dystrophy |
c.266_281del | p.Asn89fs | Pathogenic | ★☆☆☆ | LAMA2-related muscular dystrophy |
c.283+2T>C | - | Pathogenic | ★☆☆☆ | LAMA2-related muscular dystrophy |
c.3349del | p.Thr1117fs | Pathogenic | ★☆☆☆ | LAMA2-related 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 LAMA2-related muscular dystrophy, often referred to as merosin-deficient congenital muscular dystrophy [PMID:10091176]. This condition is characterised by muscle weakness and wasting, typically affecting skeletal muscles. The presentation can vary significantly, from a severe form that manifests early in life to a milder, later-onset form. The severity often depends on the specific variant and its impact on laminin protein function. The LAMA2 gene is also associated with conditions such as Cholangiocarcinoma and Limb-girdle muscular dystrophy.
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 in several Gene Panels within the UK's National Health Service (NHS) Genomic Medicine Service, as listed on PanelApp. These include panels for Arthrogryposis, Congenital muscular dystrophy, Foetal anomalies, Intellectual disability, and Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. It is also part of the Malformations of cortical development panel and the DDG2P (Developmental Disorders Genotype-Phenotype) database, indicating its established role in these clinical areas.
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, particularly laminin-211 (merosin) and laminin-221. These proteins are crucial components of the extracellular matrix, helping to maintain the stability and integrity of muscle fibres and other tissues.
What health conditions are associated with variants in the LAMA2 gene?
Variants in the LAMA2 gene are primarily associated with LAMA2-related muscular dystrophy, also known as merosin-deficient congenital muscular dystrophy. This condition causes weakness and wasting of skeletal muscles and can vary in severity.
How is LAMA2-related muscular dystrophy inherited?
LAMA2-related muscular dystrophy is inherited in an autosomal recessive manner. This means that an individual must inherit two altered copies of the LAMA2 gene, one from each parent, to develop the condition.
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