Severe cognitive impairment in DMD: obvious clinical evidence for Dp71 isoform point mutations screening

Moizard, Marie‐Pierre; Toutain, Annick; Fournier, Delphine; Berret, Françoise; Raynaud, Martine; Billard, C.; Andres, Christian R.; Moraine, Claude

doi:10.1038/sj.ejhg.5200488

Cited by 101 publications

(82 citation statements)

References 31 publications

(38 reference statements)

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“…Supporting our results, it has been observed that Dp71 protein expression increased in parallel with brain development [30]. Furthermore, C-terminal mutations in dystrophin, which would adversely affect Dp71 expression, are associated with mental retardation [35], indicating that Dp71 plays a role in central nervous system development. Nevertheless, preliminary examination on Dp71-null mice has not yet detected conspicuous morphological or histological abnormalities in central nervous system development when compared with wild type mice [40].…”

Section: Discussionsupporting

confidence: 89%

Dystrophin Dp71 is required for neurite outgrowth in PC12 cells

Acosta

2004

Experimental Cell Research

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:To determine the role of Dp71 in neuronal cells, we generated PC12 cell lines in which Dp71 protein levels were controlled by stable transfection with either antisense or sense constructs. Cells expressing the antisense Dp71 RNA (antisense-Dp71 cells) contained reduced amounts of the two endogenous Dp71 isoforms. Antisense-Dp71 cells exhibited a marked suppression of neurite outgrowth upon the induction with NGF or dibutyryl cyclic AMP. Early responses to NGF-induced neuronal differentiation, such as the cessation of cell division and the activation of ERK1/2 proteins, were normal in the antisense-Dp71 cells. On contrary, the induction of MAP2, a late differentiation marker, was disturbed in these cells. Additionally, the deficiency of Dp71 correlated with an altered expression of the dystrophin-associated protein complex (DAPC) members a and h dystrobrevins. Our results indicate that normal expression of Dp71 is essential for neurite outgrowth in PC12 cells and constitute the first direct evidence implicating Dp71 in a neuronal function. D 2004 Elsevier Inc. All rights reserved.

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Section: Discussionsupporting

confidence: 89%

Dystrophin Dp71 is required for neurite outgrowth in PC12 cells

Acosta

2004

Experimental Cell Research

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“…All the female patients with cognitive impairment except one (86%) had a mutation in the end part of the dystrophin gene, involving Dp140 or Dp71 as previously reported in several series of DMD male patients. 26,42,43 These findings therefore provide additional arguments in favor of the crucial role of Dp71 and Dp140 in the development of cognitive function.…”

Section: Muscle Study and Protein Expression In The Musclementioning

confidence: 70%

Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age

et al. 2013

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The molecular basis underlying the clinical variability in symptomatic Duchenne muscular dystrophy (DMD) carriers are still to be precised. We report 26 cases of early symptomatic DMD carriers followed in the French neuromuscular network. Clinical presentation, muscular histological analysis and type of gene mutation, as well as X-chromosome inactivation (XCI) patterns using DNA extracted from peripheral blood or muscle are detailed. The initial symptoms were significant weakness (88%) or exercise intolerance (27%). Clinical severity varied from a Duchenne-like progression to a very mild Becker-like phenotype. Cardiac dysfunction was present in 19% of the cases. Cognitive impairment was worthy of notice, as 27% of the carriers are concerned. The muscular analysis was always contributive, revealing muscular dystrophy (83%), mosaic in immunostaining (81%) and dystrophin abnormalities in western blot analysis (84%). In all, 73% had exonic deletions or duplications and 27% had point mutations. XCI pattern was biased in 62% of the cases. In conclusion, we report the largest series of manifesting DMD carriers at pediatric age and show that exercise intolerance and cognitive impairment may reveal symptomatic DMD carriers. The complete histological and immunohistological study of the muscle is the key of the diagnosis leading to the dystrophin gene analysis. Our study shows also that cognitive impairment in symptomatic DMD carriers is associated with mutations in the distal part of the DMD gene. XCI study does not fully explain the mechanisms as well as the wide spectrum of clinical phenotype, though a clear correlation between the severity of the phenotype and inactivation bias was observed. European Journal of Human Genetics (2013) 21, 855-863; doi:10.1038/ejhg.2012.269; published online 9 January 2013 Keywords: dystrophin; female carrier; X inactivation INTRODUCTION Duchenne muscular dystrophy (DMD) has always been extensively described in its clinical presentation, evolution and severity. 1 However, recent studies pointed out that the same mutation can be responsible for DMD phenotypes of different severity suggesting involvement of modifier and/or epigenetic factors. 2,3 It has been estimated that about 8% of DMD female carriers have some manifestations including cardiomyopathy and/or some degree of weakness that could be highlighted by careful clinical examination. [4][5][6][7][8] Relationships between clinical phenotype and dystrophin abnormalities in muscle tissue among female carriers of DMD gene mutations were previously investigated. 9 However, a comprehensive view of factors underlying clinical symptoms occurrence and severity is still lacking.

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“…Studies of the DGC in brain have addressed mainly its role in mediating brain abnormalities and mental retardation affecting numerous patients with congenital muscle dystrophies, as well as its role in synapse formation and plasticity [141][142][143][144][145][146]. Members of the DGC are present in specific neurons, astrocytes, and radial glia [19,23,26,30,35,37,64,145,[147][148][149][150][151][152][153][154][155], usually associated with either dystrophin isoforms or with utrophin.…”

Section: Brainmentioning

confidence: 99%

Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue

Haenggi

Fritschy

2006

Cell. Mol. Life Sci.

146

110

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The dystrophin glycoprotein complex (DGC) is a multimeric protein assembly associated with either the X-linked cytoskeletal protein dystrophin or its autosomal homologue utrophin. In striated muscle cells, the DGC links the extracellular matrix to the actin cytoskeleton and mediates three major functions: structural stability of the plasma membrane, ion homeostasis, and transmembrane signaling. Mutations affecting the DGC underlie major forms of congenital muscle dystrophies. The DGC is prominent also in the central and peripheral nervous system and in tissues with a secretory function or which form barriers between functional compartments, such as the blood-brain barrier, choroid plexus, or kidney. A considerable molecular heterogeneity arises from cell-specific expression of its constituent proteins, notably short C-terminal isoforms of dystrophin. Experimentally, the generation of mice carrying targeted gene deletions affecting the DGC has clarified the interdependence of DGC proteins for assembly of the complex and revealed its importance for brain development and regulation of the 'milieu intérieur. Here, we focus on recent studies of the DGC in brain, blood-brain barrier and choroid plexus, retina, and kidney and discuss the role of dystrophin isoforms and utrophin for assembly of the complex in these tissues.

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Severe cognitive impairment in DMD: obvious clinical evidence for Dp71 isoform point mutations screening

Cited by 101 publications

References 31 publications

Dystrophin Dp71 is required for neurite outgrowth in PC12 cells

Dystrophin Dp71 is required for neurite outgrowth in PC12 cells

Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age

Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue

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