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LARGE1
LARGE xylosyl- and glucuronyltransferase 1
The LARGE1 gene provides instructions for making a protein critical for glycosylation, a process that modifies other proteins, particularly alpha-dystroglycan, which is essential for muscle stability and brain development. The LARGE1 gene encodes a glycosyltransferase enzyme located in the Golgi apparatus, where it adds sugar molecules to 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 crucial role in modifying proteins through a process called glycosylation. Specifically, the protein produced from this gene is responsible for adding chains of xylose and glucuronic acid sugars to alpha-dystroglycan, a protein important for cell structure.
Dysfunction of the LARGE1 protein can lead to severe health conditions, primarily affecting muscle function and brain development. These conditions include various forms of congenital muscular dystrophy.
What the gene does
The LARGE1 protein functions within the Golgi apparatus, a cellular organelle involved in modifying and packaging proteins. Its primary role is as a glycosyltransferase, meaning it adds sugar molecules to other proteins. A key target for LARGE1's activity is alpha-dystroglycan.
Through glycosylation, the LARGE1 protein attaches chains of xylose and glucuronic acid sugars to alpha-dystroglycan. This sugar modification is essential for alpha-dystroglycan to properly link the internal cellular scaffolding (cytoskeleton) to the external support network (extracellular matrix). In skeletal muscles, this linkage helps to stabilise and protect muscle fibres. In the brain, correctly glycosylated alpha-dystroglycan is vital for guiding the migration of nerve cells during early developmental stages.
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Chromosome location
The LARGE1 gene is located on chromosome 22, specifically at position 22q12.3. This region denotes its precise band on the long arm (q) of chromosome 22. The gene directs the production of a protein composed of 756 amino acids.
Protein structure
The LARGE1 protein consists of several functional regions crucial for its enzymatic activity. It includes a Disordered region spanning amino acids 43-69, followed by a Coiled coil domain from amino acids 53-95. Another Disordered region is found between amino acids 81-109. The protein's catalytic functions are localised to specific domains: a Xylosyltransferase activity region from amino acids 138-413 and a Glucuronyltransferase activity region spanning amino acids 414-756.
Key variants
Variants within the LARGE1 gene can lead to alterations in the structure or function of the encoded protein, affecting its ability to correctly glycosylate target proteins like alpha-dystroglycan. These changes can result in a spectrum of clinical manifestations, particularly those involving muscle and brain development.
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 | ★★☆☆ | Muscular dystrophy-dystroglycanopathy type B6 |
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 group of conditions known as congenital muscular dystrophies. The most severe of these is Walker-Warburg syndrome, characterised by profound muscle weakness and abnormalities affecting the brain and eyes. Less severe forms, such as congenital muscular dystrophy type 1D (MDC1D), also involve muscle weakness, brain abnormalities, and intellectual disability, but typically spare the eyes.
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 in several expert-curated panels within the UK National Health Service (NHS) Genomic Medicine Service's PanelApp. It is green-rated (evidence strong for pathogenicity) for conditions such as Arthrogryposis, Ataxia and cerebellar anomalies - childhood onset, Cerebellar hypoplasia, Congenital disorders of glycosylation, Congenital muscular dystrophy (R79), DDG2P, Foetal anomalies (R21), Hydrocephalus (R86), Intellectual disability, Likely inborn error of metabolism (R98), Malformations of cortical development, and Undiagnosed metabolic disorders.
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 provides instructions for making an enzyme that performs glycosylation, adding specific sugar molecules to other proteins. This process is crucial for the proper function of alpha-dystroglycan, which is vital for muscle stability and brain development.
What conditions are associated with LARGE1 gene variants?
Variants in the LARGE1 gene are associated with congenital muscular dystrophies, including severe forms like Walker-Warburg syndrome, which affects muscles, brain, and eyes, and less severe forms like congenital muscular dystrophy type 1D (MDC1D).
Where in the cell does the LARGE1 protein work?
The LARGE1 protein is primarily found in the Golgi apparatus, a cellular organelle responsible for modifying, sorting, and packaging proteins for secretion or delivery to other organelles.
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