| *603590 | |||||||||||||||||||||||||||||||||||||||||||||
| ACETYLGLUCOSAMINYLTRANSFERASE-LIKE PROTEIN; LARGE | |||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||
| KIAA0609 LIKE-GLYCOSYLTRANSFERASE | |||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: LARGE | |||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 22q12.3 Genomic coordinates (GRCh37): 22:33,669,061 - 34,316,415 (from NCBI) | |||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||
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| Cloning | |||||||||||||||||||||||||||||||||||||||||||||
| Peyrard et al. (1999) investigated the gene content of a segment of 22q12.3-q13.1 that had been shown to contain meningioma-related genes (156100) on the basis of studies of deletions. They characterized a novel member of the N-acetylglucosaminyltransferase gene family, which they designated the LARGE gene. The expression pattern of the human and mouse LARGE orthologs is similar. Both genes are expressed ubiquitously, consistent with their function as housekeeping genes. These genes are also evolutionarily well conserved, as Peyrard et al. (1999) identified an ortholog in C. elegans encoding a polypeptide that is 33% identical with the human protein. Brockington et al. (2005) noted that the 756-amino acid LARGE protein contains an N-terminal transmembrane domain, a coiled-coil domain, and 2 catalytic domains. | |||||||||||||||||||||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||||||||||||||||||||
| Peyrard et al. (1999) determined that the LARGE gene spans more than 664 kb of genomic DNA, making it the fifth largest in the human genome, after dystrophin (DMD; 300377), with 2.3 Mb; DCC (120470), with 1.4 Mb; GRM8 (601116), with 1 Mb; and utrophin (UTRN; 128240), with 900 kb. The LARGE gene contains 16 exons (4,326-bp cDNA) and has an exon content of less than 0.66%, which is similar to the exon content of the DMD gene (0.6%). | |||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||
| Peyrard et al. (1999) mapped the LARGE gene to chromosome 22q12.3-q13.1, a segment apparently poor in genes. By fluorescence in situ hybridization, Peyrard et al. (1999) mapped the mouse Large gene to 8C1 in a region of conserved synteny with 22q12.3-q13.1. | |||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||||||||||||||
| Kanagawa et al. (2004) showed that both the N-terminal domain and a portion of the mucin-like domain of alpha-dystroglycan (128239) are essential for high-affinity laminin receptor function. They found that posttranslational modification of alpha-dystroglycan by LARGE occurs within the mucin-like domain, but the N-terminal domain interacts with LARGE, defining an intracellular enzyme-substrate recognition motif necessary to initiate functional glycosylation. Gene replacement in dystroglycan-deficient muscle demonstrated that the dystroglycan C-terminal domain is sufficient only for dystrophin-glycoprotein complex assembly. To prevent muscle degeneration, expression of a functional dystroglycan through LARGE recognition and glycosylation was required. The authors concluded that molecular recognition of dystroglycan by LARGE is a key determinant in the biosynthetic pathway to produce mature and functional dystroglycan. Brockington et al. (2005) transfected various cell lines with a variety of LARGE expression constructs in order to characterize their subcellular localization and effect on alpha-dystroglycan (DAG1; 128239) glycosylation. Wildtype LARGE colocalized with the Golgi marker GM130 and stimulated alpha-dystroglycan hyperglycosylation. The 2 predicted catalytic domains of LARGE contain 3 conserved DxD motifs. Systematically mutating each of these motifs to NNN resulted in the mislocalization of 1 construct, and all failed to have any effect on alpha-dystroglycan glycosylation. A construct lacking the transmembrane domain also failed to localize at the Golgi apparatus. Brockington et al. (2005) concluded that LARGE needs to both physically interact with alpha-dystroglycan and function as a glycosyltransferase in order to stimulate alpha-dystroglycan hyperglycosylation. | |||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||
| Mutation in the LARGE gene can cause 2 different forms of muscular dystrophy-dystroglycanopathy (MDDG): a severe congenital form with brain and eye anomalies (type A6; MDDGA6, 613154), formerly designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), and a less severe congenital form with mental retardation (type B6; MDDGB6; 608840), formerly designated congenital muscular dystrophy type 1D (MDC1D). Longman et al. (2003) studied 36 patients with congenital muscular dystrophy (CMD) and either mental retardation, structural brain changes, or abnormal alpha-dystroglycan immunolabeling, who were unlinked to any known CMD loci. Among 29 families in which linkage to the LARGE gene was not excluded, sequence analysis identified 1 patient who was compound heterozygous for mutations in the LARGE gene: E509K (603590.0001) and a 1-bp insertion (1999insT; 603590.0002). The affected 17-year-old girl presented with congenital muscular dystrophy, profound mental retardation, and white matter changes and subtle structural abnormalities on brain MRI (MDDGB6; 608840). In a patient with muscle-eye-brain disease (MDDGA6; 613154), Clement et al. (2008) identified compound heterozygosity for 2 mutations in the LARGE gene (603590.0005 and S331F, 603590.0006). The patient had congenital muscular dystrophy, increased serum creatine kinase, mental retardation, and myopia. Brain MRI showed ventricular dilatation, abnormal white matter changes, cerebellar cysts, dysplastic cerebellar vermis, posterior convality of the brainstem, pontine hypoplasia with a cleft, and frontoparietal polymicrogyria. In 2 Saudi sibs with Walker-Warburg syndrome (613154), born of consanguineous parents, van Reeuwijk et al. (2007) identified a homozygous 63-kb intragenic deletion in the LARGE gene (603590.0003). In 1 of 81 Italian patients with congenital muscular dystrophy and defective glycosylation of alpha-dystroglycan, Mercuri et al. (2009) identified a homozygous mutation in the LARGE gene (W495R; 603590.0004). The phenotype was consistent with Walker-Warburg syndrome. In a patient with LARGE-related congenital muscular dystrophy, Clement et al. (2008) identified compound heterozygous mutations in the LARGE gene (603590.0007 and 603590.0001). In 2 sisters with LARGE-related congenital muscular dystrophy, Clarke et al. (2011) identified a homozygous insertion/deletion in the LARGE gene (603590.0008). Each unaffected parent was heterozygous for the mutation. | |||||||||||||||||||||||||||||||||||||||||||||
| Evolution | |||||||||||||||||||||||||||||||||||||||||||||
| Sabeti et al. (2007) reported an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2. The analysis revealed more than 300 strong candidate regions that appeared to have undergone recent natural selection. Examination of 22 of the strongest regions highlighted 3 cases in which 2 genes in a common biologic process had apparently undergone positive selection in the same population: LARGE and DMD (300377), both related to infection by the Lassa virus, in West Africa; SLC24A5 (609802) and SLC45A2 (606202), both involved in skin pigmentation, in Europe; and EDAR (604095) and EDA2R (300276), both involved in the development of hair follicles, in Asia. | |||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||||||||
| Grewal et al. (2001) found that the mouse myodystrophy (myd) mutation resides in the mouse homolog of the LARGE gene. They found that an intragenic deletion of exons 4-7 causes a frameshift in the resultant mRNA and a premature termination codon before the first of the 2 catalytic domains. On immunoblots, a monoclonal antibody to alpha-dystroglycan, a component of the dystrophin-associated glycoprotein complex (DGC), showed reduced binding in myd, which they attributed to altered glycosylation of this protein. They speculated that abnormal posttranslational modification of alpha-dystroglycan may contribute to the myd phenotype. Michele et al. (2002) demonstrated in both muscle-eye-brain disease and Fukuyama congenital muscular dystrophy (see 253800) patients that alpha-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin (see 150240), neurexin (see 600565), and agrin (103320). Michele et al. (2002) showed that this posttranslational biochemical and functional disruption of alpha-dystroglycan is recapitulated in the muscle and central nervous system of myd mice. Michele et al. (2002) demonstrated that myd mice have abnormal neuronal migration in the cerebral cortex, cerebellum, and hippocampus, and show disruption of the basal lamina. In addition, myd mice reveal that dystroglycan targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. Michele et al. (2002) suggested that at least 3 mammalian genes function within a convergent posttranslational processing pathway during the biosynthesis of dystroglycan and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities. Holzfeind et al. (2002) showed that the muscular dystrophy phenotype is not confined to skeletal muscle in the myd (Large-myd) mouse. Immunohistochemistry indicated disruption of the dystrophin-associated glycoprotein complex in skeletal and cardiac muscle. Mutant skeletal muscle showed a general increase in the expression of DGC proteins and of dysferlin (DYSF; 603009) and caveolin-3 (CAV3; 601253). In contrast, the expression of DGC proteins was reduced in cardiac muscle. Overlay assays showed loss of laminin (LAM1; 150320) binding by alpha-dystroglycan in Large-myd skeletal and cardiac muscle and in brain. Electroretinograms of homozygous mutant mice showed gross abnormalities of b-wave characteristics, indicative of a complex defect in retinal transmission. The laminar architecture of the cortices of the cerebrum and the cerebellum was disturbed, suggesting defective neuronal migration. Glycosyltransferase deficiency is a pathogenic mechanism that has been identified in several congenital muscular dystrophies and results in abnormal glycosylation of alpha-dystroglycan. In myd mice, Barresi et al. (2004) found that overexpression of transduced Large ameliorated the dystrophic phenotype and induced synthesis of glycan-enriched alpha-DG with high affinity for extracellular ligands. In myoblasts from patients with Fukuyama muscular dystrophy, muscle-eye-brain disease, and Walker-Warburg syndrome, overexpression of LARGE resulted in increased expression of glycosylated alpha-DG and organization of laminin on the cell surface. The findings suggested that LARGE does not activate the mutant enzyme in each disorder, but that it is an essential component of the glycosylation machinery of alpha-DG. Rando (2004) reviewed this approach to the treatment of muscular dystrophies by enhancing glycosylation. | |||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||||||||||||||
| .0001 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 6 | |||||||||||||||||||||||||||||||||||||||||||||
| LARGE, GLU509LYS [dbSNP:rs121908675] | |||||||||||||||||||||||||||||||||||||||||||||
| In a 17-year-old girl with congenital muscular dystrophy, profound mental retardation, white matter changes, and subtle brain structural abnormalities (MDDGB6; 608840), Longman et al. (2003) identified compound heterozygosity for mutations in the LARGE gene. One mutation was a 1525G-A transition in exon 13 resulting in a substitution of lysine for glutamate-509, a highly conserved residue in the putative second catalytic domain; the other was a 1-bp insertion (1999insT; 603590.0002) in exon 15, predicted to result in a frameshift and premature stop signal at codon 693, truncating the putative second catalytic domain. The patient's skeletal muscle biopsy showed reduced immunolabeling of alpha-dystroglycan. Immunoblotting with an antibody to a glycosylated epitope demonstrated a reduced molecular weight form of alpha-dystroglycan that retained some laminin-binding activity. Brockington et al. (2005) showed that LARGE mutants E509K and 1999insT had no effect on alpha-dystroglycan glycosylation and failed to localize correctly to the Golgi apparatus, confirming their pathogenicity. In a patient with LARGE-related congenital muscular dystrophy and mental retardation (608840), Clement et al. (2008) identified compound heterozygosity for 2 mutations in the LARGE gene: E509K and a frameshift (667fs; 603590.0007). The patient was a 14-year-old individual with had mental retardation, nystagmus, abnormal electroretinogram, and increased serum creatine kinase. Brain MRI showed periventricular and temporal white matter changes, posterior concavity of the brainstem, hypoplastic pons, and frontoparietal pachygyria. The patient was identified in a larger study of 27 patients with a dystroglycanopathy. | |||||||||||||||||||||||||||||||||||||||||||||
| .0002 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 6 | |||||||||||||||||||||||||||||||||||||||||||||
| LARGE, 1-BP INS, 1999T | |||||||||||||||||||||||||||||||||||||||||||||
| See 603590.0001 and Longman et al. (2003). | |||||||||||||||||||||||||||||||||||||||||||||
| .0003 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 6 | |||||||||||||||||||||||||||||||||||||||||||||
| LARGE, 63-KB DEL | |||||||||||||||||||||||||||||||||||||||||||||
| In 2 Saudi sibs with Walker-Warburg syndrome (MDDGA6; 613154), born of consanguineous parents, van Reeuwijk et al. (2007) identified a homozygous 63-kb intragenic deletion in the LARGE gene, including part of intron 8, exon 9, intron 9, exon 10, and most of intron 10. At birth, both showed severe hypotonia, absent deep tendon reflexes, widened anterior fontanels, and ophthalmic changes, including cataract, optic atrophy, and retinal dysplasia. Both had increased serum creatine kinase and dystrophic muscle biopsies. Brain CT scan showed ventricular dilatation, absence of the inferior cerebellar vermis, and hypoplastic cerebellum; 1 of the sibs had hydrocephalus and Dandy-Walker malformation. The sibs died at age 6 and 2 months, respectively. The unaffected parents were heterozygous for the deletion. | |||||||||||||||||||||||||||||||||||||||||||||
| .0004 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 6 | |||||||||||||||||||||||||||||||||||||||||||||
| LARGE, TRP495ARG | |||||||||||||||||||||||||||||||||||||||||||||
| In a patient with Walker-Warburg syndrome (MDDGA6; 613154), Mercuri et al. (2009) identified a homozygous 1483T-C transition in the LARGE gene, resulting in a trp495-to-arg (W495R) substitution in a highly conserved residue needed to correct nucleotide-disphosphosugar transferase activity. The patient had increased serum creatine kinase, absent alpha-dystroglycan (128239) on muscle biopsy, mental retardation, and had only achieved head control. | |||||||||||||||||||||||||||||||||||||||||||||
| .0005 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 6 | |||||||||||||||||||||||||||||||||||||||||||||
| LARGE, GLN87FS | |||||||||||||||||||||||||||||||||||||||||||||
| In a patient with muscle-eye-brain disease (MDGGA6; 613154), Clement et al. (2008) identified compound heterozygosity for 2 mutations in the LARGE gene: 1 resulting in a frameshift at gln87, and the other in a ser331-to-phe substitution (S331F; 603590.0006). The patient had congenital muscular dystrophy, increased serum creatine kinase, mental retardation, and myopia. Brain MRI showed ventricular dilatation, abnormal white matter changes, cerebellar cysts, dysplastic cerebellar vermis, posterior convality of the brainstem, pontine hypoplasia with a cleft, and frontoparietal polymicrogyria. | |||||||||||||||||||||||||||||||||||||||||||||
| .0006 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 6 | |||||||||||||||||||||||||||||||||||||||||||||
| LARGE, SER331PHE | |||||||||||||||||||||||||||||||||||||||||||||
| See 603590.0005 and Clement et al. (2008). | |||||||||||||||||||||||||||||||||||||||||||||
| .0007 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 6 | |||||||||||||||||||||||||||||||||||||||||||||
| LARGE, 667FS | |||||||||||||||||||||||||||||||||||||||||||||
| See 603590.0001 and Clement et al. (2008). | |||||||||||||||||||||||||||||||||||||||||||||
| .0008 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION), TYPE B, 6 | |||||||||||||||||||||||||||||||||||||||||||||
| LARGE, 42.9-KB INS/4.1-KB DEL | |||||||||||||||||||||||||||||||||||||||||||||
| In 2 sisters, born of consanguineous Lebanese parents with congenital muscular dystrophy-dystroglycanopathy with mental retardation (608840), Clarke et al. (2011) identified a homozygous 40.8- to 42.9-kb insertion between exons 10 and 11 of the LARGE gene, predicted to introduce a premature stop codon in the mRNA transcript, resulting in truncation of the LARGE protein midway through translation. The insertion was associated with 3.0- to 4.1-kb deletion of a central region of intron 10, but the exact breakpoints of the deletion/insertion were not found, suggesting that an even more complex rearrangement may have occurred. The abnormal insertion sequence mapped to a part of a spliced EST normally located 100-kb centromeric to the LARGE gene. The girls had moderate mental retardation, marked cerebellar hypoplasia, dilated ventricles, and white matter abnormalities; 1 had pachygyria. | |||||||||||||||||||||||||||||||||||||||||||||
| See Also: | |||||||||||||||||||||||||||||||||||||||||||||
| Godfrey et al. (2007) | |||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||
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