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LARGE1
LARGE xylosyl- and glucuronyltransferase 1
The LARGE1 gene provides instructions for making a protein involved in glycosylation, a process crucial for muscle and brain development, and is associated with congenital muscular dystrophies. The LARGE1 gene encodes an enzyme vital for adding sugar molecules to other proteins, particularly alpha-dystroglycan.
LARGE1 is located on the long (q) arm of chromosome 22, at band 22q12.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The LARGE1 gene, also known as LARGE xylosyl- and glucuronyltransferase 1, plays a critical role in cellular function, particularly in the modification of proteins. It is integral to a process called glycosylation, where specific sugar molecules are attached to target proteins. This modification is vital for the proper function of tissues, especially muscle and brain. Variants in the LARGE1 gene can lead to severe developmental disorders affecting these systems.
What the gene does
The protein produced from the LARGE1 gene is situated within the Golgi apparatus, an organelle where proteins undergo essential modifications after their synthesis. Here, the LARGE1 protein acts as a glycosyltransferase, adding chains of xylose and glucuronic acid sugar molecules to other proteins. A key target of this activity is alpha-dystroglycan. Normal glycosylation of alpha-dystroglycan is fundamental for its role in anchoring the cell's internal structural framework (cytoskeleton) to the extracellular matrix. In muscle tissue, glycosylated alpha-dystroglycan helps stabilise and protect muscle fibres, while in the brain, it aids in the migration of nerve cells during early development.
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Chromosome location
The LARGE1 gene is located on the long arm of chromosome 22, at position 12.3, denoted as 22q12.3. This specific chromosomal address helps geneticists locate and study the gene within the human genome.
Protein structure
The LARGE1 protein consists of 756 amino acids and features several distinct regions. These include a Disordered region spanning amino acids 43-69, followed by a Coiled coil domain from amino acids 53-95, and another Disordered region between amino acids 81-109. Importantly, the protein contains two enzymatic domains: a Xylosyltransferase activity region from amino acids 138-413, and a Glucuronyltransferase activity region from amino acids 414-756. These domains are responsible for the protein's ability to add specific sugar molecules during glycosylation.
Key variants
Variants within the LARGE1 gene can affect the protein's ability to correctly glycosylate target proteins. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, and their impact can vary depending on where they occur within the gene and how they alter the resulting protein's function. The clinical significance of these variants is often assessed in the context of specific inherited conditions.
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.1525G>A | p.Glu509Lys | Pathogenic/Likely pathogenic | ★★☆☆ | LARGE1-Related Disorders |
c.283C>T | p.Arg95Ter | Pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy type B6 |
GRCh37/hg19 22q12.3(chr22:33655597-34281098)x1 | - | Pathogenic | ★☆☆☆ | not specified |
g.(?_33670413)_(33828271_?)del | - | Pathogenic | ★☆☆☆ | Muscular dystrophy-dystroglycanopathy type B6 |
g.(?_33700195)_(33780310_?)del | - | Pathogenic | ★☆☆☆ | Muscular dystrophy-dystroglycanopathy type B6 |
g.(?_33777885)_(33780310_?)del | - | Pathogenic | ★☆☆☆ | Muscular dystrophy-dystroglycanopathy type B6 |
g.(33828252_33960833)_(34157546_34252727)del | - | Pathogenic | ★☆☆☆ | LARGE1-Related Disorders |
g.(?_33960814)_(34000564_?)del | - | Pathogenic | ★☆☆☆ | Muscular dystrophy-dystroglycanopathy type B6 |
c.181dup | p.Glu61fs | Pathogenic | ★☆☆☆ | Muscular dystrophy-dystroglycanopathy type B6 |
c.1890G>A | p.Trp630Ter | Pathogenic | ★☆☆☆ | Muscular dystrophy-dystroglycanopathy type B6 |
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 LARGE1 gene are primarily associated with a spectrum of congenital muscular dystrophies. These include severe conditions such as Walker-Warburg syndrome, which typically presents with significant muscle weakness, brain abnormalities, and eye involvement. Less severe forms, like congenital muscular dystrophy type 1D (MDC1D), also result from LARGE1 variants, causing muscle weakness, brain abnormalities, and intellectual disability, though generally without eye issues.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic LARGE1 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 LARGE1 gene is included on several UK National Health Service (NHS) Genomic Medicine Service national test directories. It is listed on panels for conditions such as Arthrogryposis, Ataxia and cerebellar anomalies - childhood onset, Cerebellar hypoplasia, Congenital disorders of glycosylation, Congenital muscular dystrophy, Foetal anomalies, Hydrocephalus, Intellectual disability, Likely inborn error of metabolism, Malformations of cortical development, and Undiagnosed metabolic disorders, indicating its clinical relevance in the UK for these health areas.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the LARGE1 gene?
The LARGE1 gene produces an enzyme called LARGE xylosyl- and glucuronyltransferase 1, which is responsible for adding specific sugar molecules to other proteins, particularly alpha-dystroglycan. This process, known as glycosylation, is crucial for the normal function of muscles and brain tissue.
What health conditions are associated with variants in the LARGE1 gene?
Variants in the LARGE1 gene are associated with congenital muscular dystrophies, including severe forms like Walker-Warburg syndrome and less severe forms such as congenital muscular dystrophy type 1D (MDC1D). These conditions primarily affect muscle strength and may also impact brain development and function.
How does LARGE1 affect muscle and brain development?
The protein encoded by LARGE1 ensures that alpha-dystroglycan is properly glycosylated. In muscles, this glycosylated protein helps stabilise muscle fibres, protecting them from damage. In the brain, it plays a role in guiding nerve cell migration during early development, which is essential for proper brain structure and function.
References
- Yoshida-Moriguchi T, Campbell KP. Matriglycan: a novel polysaccharide that links dystroglycan to the basement membrane. Glycobiology. 2015. PMID: 25882296
- Inamori K, Willer T, Hara Y. Endogenous glucuronyltransferase activity of LARGE or LARGE2 required for functional modification of α-dystroglycan in cells and tissues. The Journal of biological chemistry. 2014. PMID: 25138275
- Inamori K, Yoshida-Moriguchi T, Hara Y. Dystroglycan function requires xylosyl- and glucuronyltransferase activities of LARGE. Science (New York, N.Y.). 2012. PMID: 22223806
- Vuillaumier-Barrot S, Bouchet-Seraphin C, Chelbi M. Intragenic rearrangements in LARGE and POMGNT1 genes in severe dystroglycanopathies. Neuromuscular disorders : NMD. 2011. PMID: 21727005
- van Reeuwijk J, Grewal PK, Salih MA. Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome. Human genetics. 2007. PMID: 17436019
- Longman C, Brockington M, Torelli S. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Human molecular genetics. 2003. PMID: 12966029