Dystroglycanopathies: coming into focus

Godfrey, Caroline; Foley, A. Reghan; Clement, Emma; Muntoni, Francesco

doi:10.1016/j.gde.2011.02.001

Cited by 225 publications

(192 citation statements)

References 49 publications

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“…Congenital deficiencies in all of the genes involved in O-Man glycosylation produce muscular dystrophy phenotypes (42), but it is premature to identify phenotypic characteristics ascribable to other O-Man glycoproteins such as cadherins and plexins. However, it is clear that both families of proteins serve a range of essential functions that could be part of the phenotypes observed.…”

Section: Resultsmentioning

confidence: 99%

Mining the O-mannose glycoproteome reveals cadherins as major O-mannosylated glycoproteins

Vester-Christensen¹,

Halim²,

Joshi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

148

187

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The metazoan O-mannose (O-Man) glycoproteome is largely unknown. It has been shown that up to 30% of brain O-glycans are of the O-Man type, but essentially only alpha-dystroglycan (α-DG) of the dystrophin-glycoprotein complex is well characterized as an O-Man glycoprotein. Defects in O-Man glycosylation underlie congenital muscular dystrophies and considerable efforts have been devoted to explore this O-glycoproteome without much success. Here, we used our SimpleCell strategy using nuclease-mediated gene editing of a human cell line (MDA-MB-231) to reduce the structural heterogeneity of O-Man glycans and to probe the OMan glycoproteome. In this breast cancer cell line we found that O-Man glycosylation is primarily found on cadherins and plexins on β-strands in extracellular cadherin and Ig-like, plexin and transcription factor domains. The positions and evolutionary conservation of O-Man glycans in cadherins suggest that they play important functional roles for this large group of cell adhesion glycoproteins, which can now be addressed. The developed O-Man SimpleCell strategy is applicable to most types of cell lines and enables proteome-wide discovery of O-Man protein glycosylation.POMGnT1 | O-glycosylation | Orbitrap | mass spectrometry | glycoproteomics

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Section: Resultsmentioning

confidence: 99%

Mining the O-mannose glycoproteome reveals cadherins as major O-mannosylated glycoproteins

Vester-Christensen¹,

Halim²,

Joshi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

148

187

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“…[1][2][3][4] Such disorders are caused by mutations in genes coding for glycosyltransferases or accessory proteins of glycosyltransferases including protein O-mannosyltransferase 1 (POMT1, MIM 607423), protein O-mannosyltransferase 2 (POMT2, MIM 607439), protein O-mannose b-1,2-N-acetylglucosaminyltransferase (POMGNT1, MIM 606822), fukutin (FKTN; MIM 607440), fukitin-related protein (FKRP, MIM 606596), acetylglucosaminyltransferase-like protein (LARGE, MIM 603590), isoprenoid synthase domaincontaining protein (ISPD, MIM 614631), glycosyltransferase-like domain-containing protein 2 (GTDC2, MIM 147730), b-1,3-Nacetylglucosaminyltransferase 1 (B3GNT1, MIM 605517), GDP-mannose pyrophosphorylase B (GMPPB, MIM 615320), protein kinase-like protein sgk196 (SGK196, MIM 615247) and transmembrane protein 5 (TMEM5, MIM 605862). Additional genes link congenital muscular dystrophy with congenital disorders of glycosylation (DOLK, MIM 610746; DPM1, MIM 603503; DPM2, MIM 603564; and DPM3, MIM 605951).…”

Section: Introductionmentioning

confidence: 99%

B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations

2013

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Congenital muscular dystrophies associated with brain malformations are a group of disorders frequently associated with aberrant glycosylation of a-dystroglycan. They include disease entities such a Walker-Warburg syndrome, muscle-eye-brain disease and various other clinical phenotypes. Different genes involved in glycosylation of a-dystroglycan are associated with these dystroglycanopathies. We describe a 5-year-old girl with psychomotor retardation, ataxia, spasticity, muscle weakness and increased serum creatine kinase levels. Immunhistochemistry of skeletal muscle revealed reduced glycosylated a-dystroglycan. Magnetic resonance imaging of the brain at 3.5 years of age showed increased T2 signal from supratentorial and infratentorial white matter, a hypoplastic pons and subcortical cerebellar cysts. By whole exome sequencing, the patient was identified to be compound heterozygous for a one-base duplication and a missense mutation in the gene B3GALNT2 (b-1,3-N-acetylgalactosaminyltransferase 2; B3GalNAc-T2). This patient showed a milder phenotype than previously described patients with mutations in the B3GALNT2 gene.

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“…15 These phenotypes were also found to be among the most frequent in the large UK study. [16][17][18] All the cases identified as dystroglycanopathies were further subdivided according to the gene mutations. POMT1 mutations were the most frequent, followed by FKRP, POMGnT1, and POMT2.…”

mentioning

confidence: 99%

Prevalence of congenital muscular dystrophy in Italy

et al. 2015

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Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy.Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. Results:The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with a-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin a2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Conclusions:Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries. The term congenital muscular dystrophy (CMD) classically includes a group of genetically, clinically, and biochemically distinct entities sharing clinical and pathologic features such as early presentation of weakness and hypotonia and dystrophic features on muscle biopsy. 1 The rapidly increasing identification of several genes responsible for different forms of CMD has dramatically expanded the spectrum of the known forms, allowing a better understanding of the individual forms and different underlying pathomechanisms. 2 The incidence and prevalence of CMD in populations is not sufficiently known with only a few studies reporting incidence or point prevalence in relatively small regions. 3-5 Furthermore, several new genes have only been described in the last few years and the subtyping and classification in those reports is therefore not updated.

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Dystroglycanopathies: coming into focus

Cited by 225 publications

References 49 publications

Mining the O-mannose glycoproteome reveals cadherins as major O-mannosylated glycoproteins

Mining the O-mannose glycoproteome reveals cadherins as major O-mannosylated glycoproteins

B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations

Prevalence of congenital muscular dystrophy in Italy

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