Alternative titles; symbols
HGNC Approved Gene Symbol: LARGE1
Cytogenetic location: 22q12.3 Genomic coordinates (GRCh38): 22:33,066,663-33,922,824 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.3 | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 6 | 613154 | Autosomal recessive | 3 |
| Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 6 | 608840 | Autosomal recessive | 3 |
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 (see MN1, 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.
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%).
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.
Kanagawa et al. (2004) showed that both the N-terminal domain and a portion of the mucin-like domain of alpha-dystroglycan (DAG1; 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 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.
Inamori et al. (2012) found that LARGE could act as a bifunctional glycosyltransferase, with both xylosyltransferase and glucuronyltransferase activities, which produced repeating units of [-3-xylose-alpha-1,3-glucuronic acid-beta-1-]. This modification allowed alpha-dystroglycan to bind laminin-G-domain-containing extracellular matrix ligands.
LARGE is a dual-function glycosyltransferase that adds a glycan repeat to the basement membrane receptor dystroglycan. Goddeeris et al. (2013) demonstrated that coordinated upregulation of LARGE and dystroglycan in differentiating mouse muscle facilitates rapid extension of LARGE-glycan repeat chains. Using synthesized LARGE-glycan repeats, Goddeeris et al. (2013) showed a direct correlation between LARGE-glycan extension and its binding capacity for extracellular matrix ligands. Blocking LARGE upregulation during muscle regeneration results in the synthesis of dystroglycan with minimal LARGE-glycan repeats in association with a less compact basement membrane, immature neuromuscular junctions, and dysfunctional muscle predisposed to dystrophy. This was consistent with the finding that patients with increased clinical severity of disease have fewer LARGE-glycan repeats. Goddeeris et al. (2013) concluded that the LARGE-glycan of dystroglycan serves as a tunable extracellular matrix protein scaffold, the extension of which is required for normal skeletal muscle function.
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 impaired intellectual development (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: a frameshift (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 concavity of the brainstem, pontine hypoplasia with a cleft, and frontoparietal polymicrogyria.
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 (603590.0003).
In 1 of 81 Italian patients with congenital muscular dystrophy and defective glycosylation of alpha-dystroglycan (MDDGA6), 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 (MDDGB6), Clement et al. (2008) identified compound heterozygous mutations in the LARGE gene: a frameshift (603590.0007) and E509K (603590.0001).
In 2 sisters with LARGE-related congenital muscular dystrophy (MDDGB6), Clarke et al. (2011) identified a homozygous insertion/deletion in the LARGE gene (603590.0008). Each unaffected parent was heterozygous for the mutation.
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.
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 MDDGA4, 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.
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 (E509K), 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 MDDGB6, 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 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.
For discussion of the 1-bp insertion in the LARGE gene (1999insT) that was found in compound heterozygous state in a patient with congenital muscular dystrophy, profound mental retardation, white matter changes, and subtle brain structural abnormalities (MDDGB6; 608840) by Longman et al. (2003), see 603590.0001.
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.
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 (DAG1; 128239) on muscle biopsy, and mental retardation, and had only achieved head control.
In a patient with muscle-eye-brain disease (MDDGA6; 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 concavity of the brainstem, pontine hypoplasia with a cleft, and frontoparietal polymicrogyria.
For discussion of the ser331-to-phe (S331F) mutation in the LARGE gene that was found in compound heterozygous state in a patient with muscle-eye-brain disease (MDDGA6; 613154) by Clement et al. (2008), see 603590.0005.
For discussion of the frameshift mutation (667fs) in the LARGE gene that was found in compound heterozygous state in a patient with LARGE-related congenital muscular dystrophy and mental retardation (MDDGB6; 608840) by Clement et al. (2008), see 603590.0001.
In 2 sisters, born of consanguineous Lebanese parents with congenital muscular dystrophy-dystroglycanopathy with mental retardation (MDDGB6; 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.
Barresi, R., Michele, D. E., Kanagawa, M., Harper, H. A., Dovico, S. A., Satz, J. S., Moore, S. A., Zhang, W., Schachter, H., Dumanski, J. P., Cohn, R. D., Nishino, I., Campbell, K. P. LARGE can functionally bypass alpha-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nature Med. 10: 696-703, 2004. [PubMed: 15184894] [Full Text: https://doi.org/10.1038/nm1059]
Brockington, M., Torelli, S., Prandini, P., Boito, C., Dolatshad, N. F., Longman, C., Brown, S. C., Muntoni, F. Localization and functional analysis of the LARGE family of glycosyltransferases: significance for muscular dystrophy. Hum. Molec. Genet. 14: 657-665, 2005. [PubMed: 15661757] [Full Text: https://doi.org/10.1093/hmg/ddi062]
Clarke, N. F., Maugenre, S., Vandebrouck, A., Urtizberea, J. A., Willer, T., Peat, R. A., Gray, F., Bouchet, C., Manya, H., Vuillaumier-Barrot, S., Endo, T., Chouery, E., Campbell, K. P., Megarbane, A., Guicheney, P. Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene. Europ. J. Hum. Genet. 19: 452-457, 2011. [PubMed: 21248746] [Full Text: https://doi.org/10.1038/ejhg.2010.212]
Clement, E., Mercuri, E., Godfrey, C., Smith, J., Robb, S., Kinali, M., Straub, V., Bushby, K., Manzur, A., Talim, B., Cowan, F., Quinlivan, R., and 10 others. Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. Ann. Neurol. 64: 573-582, 2008. [PubMed: 19067344] [Full Text: https://doi.org/10.1002/ana.21482]
Goddeeris, M. M., Wu, B., Venzke, D., Yoshida-Moriguchi, T., Saito, F., Matsumura, K., Moore, S. A., Campbell, K. P. LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy. Nature 503: 136-140, 2013. [PubMed: 24132234] [Full Text: https://doi.org/10.1038/nature12605]
Grewal, P. K., Holzfeind, P. J., Bittner, R. E., Hewitt, J. E. Mutant glycosyltransferase and altered glycosylation of alpha-dystroglycan in the myodystrophy mouse. Nature Genet. 28: 151-154, 2001. [PubMed: 11381262] [Full Text: https://doi.org/10.1038/88865]
Holzfeind, P. J., Grewal, P. K., Reitsamer, H. A., Kechvar, J., Lassmann, H., Hoeger, H., Hewitt, J. E., Bittner, R. E. Skeletal, cardiac and tongue muscle pathology, defective retinal transmission, and neuronal migration defects in the Large(myd) mouse defines a natural model for glycosylation-deficient muscle-eye-brain disorders. Hum. Molec. Genet. 11: 2673-2687, 2002. [PubMed: 12354792] [Full Text: https://doi.org/10.1093/hmg/11.21.2673]
Inamori, K., Yoshida-Moriguchi, T., Hara, Y., Anderson, M. E., Yu, L., Campbell, K. P. Dystroglycan function requires xylosyl- and glucuronyltransferase activities of LARGE. Science 335: 93-96, 2012. [PubMed: 22223806] [Full Text: https://doi.org/10.1126/science.1214115]
Kanagawa, M., Saito, F., Kunz, S., Yoshida-Moriguchi, T., Barresi, R., Kobayashi, Y. M., Muschler, J., Dumanski, J. P., Michele, D. E., Oldstone, M. B. A., Campbell, K. P. Molecular recognition by LARGE is essential for expression of functional dystroglycan. Cell 117: 953-964, 2004. [PubMed: 15210115] [Full Text: https://doi.org/10.1016/j.cell.2004.06.003]
Longman, C., Brockington, M., Torelli, S., Jimenez-Mallebrera, C., Kennedy, C., Khalil, N., Feng, L., Saran, R. K., Voit, T., Merlini, L., Sewry, C. A., Brown, S. C., Muntoni, F. 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. Hum. Molec. Genet. 12: 2853-2861, 2003. [PubMed: 12966029] [Full Text: https://doi.org/10.1093/hmg/ddg307]
Mercuri, E., Messina, S., Bruno, C., Mora, M., Pegoraro, E., Comi, G. P., D'Amico, A., Aiello, C., Biancheri, R., Berardinelli, A., Boffi, P., Cassandrini, D. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology 72: 1802-1809, 2009. Note: Erratum: Neurology 93: 371 only, 2019. [PubMed: 19299310] [Full Text: https://doi.org/10.1212/01.wnl.0000346518.68110.60]
Michele, D. E., Barresi, R., Kanagawa, M., Saito, F., Cohn, R. D., Satz, J. S., Dollar, J., Nishino, I., Kelley, R. I., Somer, H., Straub, V., Mathews, K. D., Moore, S. A., Campbell, K. P. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418: 417-422, 2002. [PubMed: 12140558] [Full Text: https://doi.org/10.1038/nature00837]
Peyrard, M., Seroussi, E., Sandberg-Nordqvist, A.-C., Xie, Y.-G., Han, F.-Y., Fransson, I., Collins, J., Dunham, I., Kost-Alimova, M., Imreh, S., Dumanski, J. P. The human LARGE gene from 22q12.3-q13.1 is a new, distinct member of the glycosyltransferase gene family. Proc. Nat. Acad. Sci. 96: 598-603, 1999. [PubMed: 9892679] [Full Text: https://doi.org/10.1073/pnas.96.2.598]
Rando, T. A. Artificial sweeteners--enhancing glycosylation to treat muscular dystrophies. New Eng. J. Med. 351: 1254-1256, 2004. [PubMed: 15371584] [Full Text: https://doi.org/10.1056/NEJMcibr042066]
Sabeti, P. C., Varilly, P., Fry, B., Lohmueller, J., Hostetter, E., Cotsapas, C., Xie, X., Byrne, E. H., McCarroll, S. A., Gaudet, R., Schaffner, S. F., Lander, E. S., International HapMap Consortium. Genome-wide detection and characterization of positive selection in human populations. Nature 449: 913-918, 2007. [PubMed: 17943131] [Full Text: https://doi.org/10.1038/nature06250]
van Reeuwijk, J., Grewal, P. K., Salih, M. A. M., Beltran-Valero de Bernabe, D., McLaughlan, J. M., Michielse, C. B., Herrmann, R., Hewitt, J. E., Steinbrecher, A., Seidahmed, M. Z., Shaheed, M. M., Abomelha, A., Brunner, H. G., van Bokhoven, H., Voit, T. Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome. Hum. Genet. 121: 685-690, 2007. [PubMed: 17436019] [Full Text: https://doi.org/10.1007/s00439-007-0362-y]