Defective LARGE causes MDDGA6 and MDDGB6

Glycosyltransferase-like protein LARGE (MIM:603590) is a bifunctional glycosyltransferase with both xylosyltransferase and beta-1,3-glucuronyltransferase activities involved in the biosynthesis of a phosphorylated O-mannosyl trisaccharide, a structure present in alpha-dystroglycan (DAG1; MIM:128239) which plays a key role in skeletal muscle function and regeneration. LARGE contains two substrate-specific GT-domains and belongs to the CAZy glycosyltransferase families GT8 and GT49. Defects in LARGE result in hypoglycosylation of DAG1 and cause several congenital muscular dystrophies (CMDs). Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A6 (MDDGA6; MIM:613154) is associated with brain anomalies, eye malformations, profound mental retardation, and death usually in the first years of life (Clement et al. 2008, Mercuri et al. 2009). Muscular dystrophy-dystroglycanopathy congenital with mental retardation B6 (MDDGB6; MIM:608840) is associated with profound mental retardation, white matter changes and structural brain abnormalities (Longman et al. 2003).

糖基转移酶样蛋白LARGE（MIM:603590）是一种具有双功能糖基转移酶活性的蛋白质，包括木糖基转移酶和β-1,3-葡萄糖醛酸转移酶活性，这些活性参与磷酸化O-甘露糖基三糖的生物合成。该结构存在于α-肌营养不良蛋白（DAG1；MIM:128239）中，α-肌营养不良蛋白在骨骼肌功能与再生中发挥着至关重要的作用。LARGE蛋白含有两个底物特异性GT结构域，属于CAZy糖基转移酶家族GT8和GT49。LARGE基因的缺陷导致DAG1低糖基化，进而引发多种先天性肌营养不良症（CMDs）。肌营养不良症-肌营养不良蛋白病先天性伴脑和眼畸形A6（MDDGA6；MIM:613154）与脑畸形、眼形态异常、重度智力低下及生命早期死亡有关（Clement et al. 2008，Mercuri et al. 2009）。肌营养不良症-肌营养不良蛋白病先天性伴智力低下B6（MDDGB6；MIM:608840）与重度智力低下、白质病变和脑结构异常相关（Longman et al. 2003）。