Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

Martin, Paul T.

doi:10.1038/ncpneuro0155

Cited by 40 publications

(42 citation statements)

References 62 publications

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“…The researches about the long-term potential of glycotherapies for CMD have begun with the first reports about the defective alpha-DG glycosylation as a new pathogenic mechanism for some subtypes of 7,11,13,15,[32][33][34][36][37][38][39][40][41][42][43][44][45][46][47][48]157,176,177 . The central point of these researches is that the overexpression of lArGe promotes the attachement of glycans to alpha-DG, therefore restoring its ligandbinding function 178 .…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

“…During the last seven years, many have discussed and elucidated the pathogenesis of the defective glycosylation of alpha-DG, and the particular cortical involvement that is observed in many of them 5,711,13,15,17,18,30,33,34,[36][37][38][39][40][41][42][43][44][45][46][47][157][158][159][160][161] . It is supposed that other subtypes of CMD will prove to depend on mutations in genes as yet unidentified but also involved in alpha-DG glycosylation 39,45,46,48 . In addition, from the first reports on congenital disorders of glycosylation, it seemed unlikely that the glycosyltransferases could have a role only in glycosylation of alpha-DG and the importance of looking for other protein targets has been emphasized 37,38 .…”

Section: Disorders Of Glycosylation Of Alphadg (Alpha-dystroglycanopamentioning

confidence: 99%

“…Molecular changes in genes that codified glycosyltransferases affecting this step of the DAG chain of links are responsible for the pathogenesis of five CMDs named alpha-dystroglycanopathies or CMDs by defects of the omannosyl-glycosylation of alpha-DG [1][2][3][4][5][6][7]15,30,33,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] : Fukuyama CMD (FCMD), "muscle-eye-brain" (MeB) disease, WalkerWarburg syndrome (WWs), MDC1C and MCD1D.…”

Section: Fig 1 Schematic Representation Of the Main Proteins Involvementioning

confidence: 99%

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Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Reed

2009

Arq. Neuro-Psiquiatr.

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-The congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem), CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscleeye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D), and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.Key WorDs: congenital muscular dystrophy, MDC1A, collagen VI related disorders, glycosylation of alphadystroglycan, Fukuyama DMC, muscle-eye-brain (MeB) disease, Walker-Warburg syndrome, rigid spine syndrome. distrofia muscular congênita. parte ii: revisão da patogênese e perspectivas terapêuticas resumo -As distrofias musculares congênitas (DMCs) são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. são caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. o quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. os aspectos clínicos e diagnósticos dos principais subtipos de DMC foram apresentados no número anterior deste periódico, como primeira parte desta revisão. Nesta segunda parte apresentaremos os principais mecanismos patogênicos e as perspectivas terapêuticas dos subtipos mais comuns de DMC: DMC tipo 1A com deficiência de merosina, DMCs relacionadas com alterações do colágeno VI (Ullrich e Bethlem), e DMCs com anormalidades de glicosilação da alfa-distroglicana (DMC Fukuyama, DMC "Muscle-eye-brain" ou MeB, síndrome de Walker Warburg, DMC tipo 1C, DMC tipo 1D). A DMC com espinha rígida, mais rara e não relacionada com alterações do complexo distrofina-glicoproteínas associadas-matriz extracelular também será abordada quanto aos mesmos aspectos patogênicos e terapêuticos.PAlAVrAs-ChAVes: distrofia muscular congênita, merosina, colágeno VI, glicosila...

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Section: Therapeutic Perspectivesmentioning

confidence: 99%

Section: Disorders Of Glycosylation Of Alphadg (Alpha-dystroglycanopamentioning

confidence: 99%

Section: Fig 1 Schematic Representation Of the Main Proteins Involvementioning

confidence: 99%

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Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Reed

2009

Arq. Neuro-Psiquiatr.

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“…Mutation of the LARGE gene is the rarest of the six known genetic causes (protein O-mannosyltransferase 1, protein O-mannosyltransferase 2, O-mannose β-1, 2-N-acetylglucosaminyltransferase, Fukuyama type congenital muscular dystrophy protein, Fukutin-related protein and LARGE) of α-dystroglycanopathy (αDG). Abnormality in the glycosylation of αDG is the hallmark histological abnormality and the likely pathogenic mechanism for a group of congenital muscular dystrophies, collectively termed αDGs (13). Affected children exhibit typical neurological and muscular abnormalities associated with the αDGs, but with very different severities.…”

Section: Discussionmentioning

confidence: 99%

22q12.3 microduplication overlapping the LARGE gene as a male-only affected loci responsible for increasing the risk of autism spectrum disorder

2017

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Abstract. The present study describes a three-generation Chinese family with one male who was diagnosed with an autism spectrum disorder (ASD) disease. The male proband presented with features of an autism spectrum disorder. Magnetic resonance imaging demonstrated an abnormal high-intensity zone in the frontal white matter. Whole-genome single nucleotide polymorphism-microarray demonstrated an interstitial 575-kb duplication of chromosome 22p12.3 that involved the LARGE gene among the six family members, which included three healthy female carriers, the affected boy and two male fetuses. Fluorescence in situ hybridization analysis, using special probes, and LARGE gene sequencing were performed, which exhibited a submicroscopic 22q13 duplication that involved the LARGE gene. Combined with a review of the literature, the present findings support the hypothesis that the 22q12.3 microduplication overlapping the LARGE gene may be a male-only affected loci, which is responsible for increasing the ASD risk.

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“…These include Walker-Warburg syndrome (WWS; MIM 236670), muscle-eye-brain disease (MEB, MIM 253280), Fukuyama congenital muscular dystrophy (FCMD, MIM 253800), congenital muscular dystrophy type 1C (MDC1C, MIM 606612), and congenital muscular dystrophy type 1D (MDC1D, MIM 608840). These disorders represent a continuum in severity, sharing similar clinical features that include congenital or neonatal hypotonia, ocular abnormalities, and mental retardation associated with defects in neuronal migration (reviewed by Martin 2006).…”

Section: Introductionmentioning

confidence: 99%

Novel synonymous substitution in POMGNT1 promotes exon skipping in a patient with congenital muscular dystrophy

et al. 2008

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Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy type 1C, and congenital muscular dystrophy type 1D are overlapping clinical entities belonging to a subgroup of the congenital muscular dystrophies (CMD), collectively designated dystroglycanopathies, in which the common underlying defect is hypoglycosylation of alfa-dystroglycan. Currently, six different genes are known to be implicated in these diseases: POMT1, POMT2, POMGNT1, FCMD, FKRP, and LARGE. We report the molecular characterization of a patient presenting clinical features of CMD and reduced immunostaining for alfadystroglycan in muscle. Three candidate genes (FCMD, POMT1 and POMGNT1) were analyzed, and a total of 18 sequence variants were detected: 15 polymorphisms in POMT1 [including three unreported single nucleotide polymorphisms (SNPs)], two polymorphisms in FCMD, and the exonic silent mutation c.636C [ T in POMGNT1. Expression analysis revealed that this apparently silent mutation compromises correct premessenger RNA (mRNA) splicing, promoting skipping of the entire exon 7, with a consequent frameshift. In silico analysis of this mutation did not predict alterations in the canonical splice sequences, but rather the creation of a new exonic splice silencer. The recognition of such disease-causing elements may contribute to the further understanding of RNA processing and assist mutation screening in routine diagnosis, where such changes may be underestimated. To aid clinical diagnosis, we generated publicly available LOVD-powered Locus Specific Databases for these three genes and recorded all known sequence variants (http://www.dmd.nl).

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Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

Cited by 40 publications

References 62 publications

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

22q12.3 microduplication overlapping the LARGE gene as a male-only affected loci responsible for increasing the risk of autism spectrum disorder

Novel synonymous substitution in POMGNT1 promotes exon skipping in a patient with congenital muscular dystrophy

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