Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy

Taylor, Peter J.; Betts, Grant A.; Maroulis, Sarah; Gilissen, Christian; Pedersen, Robyn L.; Mowat, David; Johnston, Heather; Buckley, Michael F.

doi:10.1371/journal.pone.0008803

Cited by 163 publications

(214 citation statements)

References 48 publications

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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: 66%

“…Indeed, these mutations include deletions of exons 51-53 and of exons 28-54, encompassing the first coding exon of Dp140 isoform (exon 51). 26 For Dp71 whose coding sequence starts at the exon 63, the mutations were nonsense mutations in exons 66 and 67, respectively. In the two other patients, DMD abnormalities correspond to one duplication of exons 61-66 and one triplication of exons 60-63 predicted to disrupt all DMD products, including Dp140 and Dp71 isoforms.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Muscle Study and Protein Expression In The Musclementioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

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

et al. 2013

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“…53,54 However, exon 45 does not affect three shorter DMD isoforms (Dp140, Dp116 and Dp71) which are known to be associated with cognitive function in DMD. 55,56 rs1800273: G4A was detected earlier in DMD patients and is present in the Leiden Muscular dystrophy database. 57 Since majority of DMD patients have cognitive impairment, the association of rs1800273:G4A with DMD may represent association with cognitive impairment.…”

Section: Discussionmentioning

confidence: 88%

The dystrophin gene and cognitive function in the general population

et al. 2014

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The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (Po1 × 10 − 4 ), rs147546024:A4G showed strong association (β = 1.786, P-value = 2.56 × 10 − 4 ) with block-design test in the ERF study, while another variant rs1800273:G4A showed suggestive association (β = − 0.465, P-value = 0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A4G is an intronic variant, whereas rs1800273:G4A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values = 0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.

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“…Considering that our mutation affects all isoforms including the two isoforms that are proven to be involved in the reduced cognitive abilities of a number of patients with DMD mutations, 10,11 we think that our mutation only mildly impairs the function of dystrophin, thereby having only a subclinical muscular phenotype, but still resulting in a relatively large effect on the cognitive abilities of the affected family members. Previously, one other single-amino-acid deletion has been reported, p.(Glu3367del), that is found C-terminally of our mutation and supposedly initiates rotational and/or translational displacement a-helix region adjacent to the ZZ domain of DMD.…”

Section: Discussionmentioning

confidence: 98%

“…The muscular dystrophy is often accompanied by intellectual disability (ID), especially in case of truncating mutations that lead to the absence of Dp71. 10,11 To our knowledge, only one patient has been described with a DMD mutation with ID, but without muscular dystrophy: a deletion of exons 3-9 affecting only the largest dystrophin isoform Dp427. 12 Here, we describe a family of six males who have nonspecific X-linked ID (XLID; MRX85), with a DMD mutation that only disturbs the shortest brain-specific isoform, Dp71.…”

Section: Introductionmentioning

confidence: 99%

A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy

Brouwer¹,

Nabuurs

Verhaart

et al. 2013

Eur J Hum Genet

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We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11-Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with b-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P ¼ 0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.

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Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy

Cited by 163 publications

References 48 publications

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

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

The dystrophin gene and cognitive function in the general population

A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy

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