LARGE1

LARGE1 is a member of the N-acetylglucosaminyltransferase gene family. It encodes a glycosyltransferase which participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. LARGE1 may also be involved in the addition of a repeated disaccharide unit. LARGE1 is the glycotransferase that adds the final xylose and glucuronic acid to alpha-dystroglycan and thereby allows alpha-dystroglycan to bind ligands including laminin 211 and neurexin. Mutations in LARGE1 cause several forms of congenital muscular dystrophy characterized by cognitive disability and abnormal glycosylation of alpha-dystroglycan.

Full Name

LARGE xylosyl- and glucuronyltransferase 1

Function

Bifunctional glycosyltransferase with both alpha-1,3-xylosyltransferase and beta-1,3-glucuronyltransferase activities involved in the maturation of alpha-dystroglycan (DAG1) by glycosylation leading to DAG1 binding to laminin G-like domain-containing extracellular proteins with high affinity (PubMed:22223806, PubMed:15752776, PubMed:15661757, PubMed:25279699, PubMed:25279697, PubMed:23125099, PubMed:21987822).
Elongates the glucuronyl-beta-1,4-xylose-beta disaccharide primer structure initiated by AC B4GAT1 by adding repeating units [-3-Xylose-alpha-1,3-GlcA-beta-1-] to produce a heteropolysaccharide (PubMed:22223806, PubMed:25279699, PubMed:25279697, PubMed:25138275, PubMed:32975514, PubMed:23125099).
Requires the phosphorylation of core M3 (O-mannosyl trisaccharide) by POMK to elongate the glucuronyl-beta-1,4-xylose-beta disaccharide primer (PubMed:21987822).
Plays a key role in skeletal muscle function and regeneration (By similarity).

Biological Process

Glycoprotein biosynthetic processManual Assertion Based On ExperimentTAS:UniProtKB
Glycosphingolipid biosynthetic processManual Assertion Based On ExperimentTAS:UniProtKB
Muscle cell cellular homeostasisISS:UniProtKB
N-acetylglucosamine metabolic processManual Assertion Based On ExperimentTAS:ProtInc
Protein glycosylationManual Assertion Based On ExperimentIMP:UniProtKB
Protein O-linked glycosylationTAS:Reactome
Protein O-linked mannosylationManual Assertion Based On ExperimentIDA:UniProtKB
Skeletal muscle organ developmentISS:UniProtKB
Skeletal muscle tissue regenerationISS:UniProtKB

Cellular Location

Golgi apparatus membrane

Involvement in disease

Muscular dystrophy-dystroglycanopathy congenital with impaired intellectual development B6 (MDDGB6):
A congenital muscular dystrophy associated with profound mental retardation, white matter changes and structural brain abnormalities. Skeletal muscle biopsies show reduced immunolabeling of alpha-dystroglycan.
Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A6 (MDDGA6):
An autosomal recessive disorder characterized by congenital muscular dystrophy associated with cobblestone lissencephaly and other brain anomalies, eye malformations, profound mental retardation, and death usually in the first years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease.

Topology

Cytoplasmic: 1-10
Helical: 11-31
Lumenal: 32-756