Mutation spectrum leading to an attenuated phenotype in dystrophinopathies

Tuffery‐Giraud, Sylvie; Saquet, Céline; Thorel, Delphine; Disset, Antoine; Rivier, François; Malcolm, Sue; Claustres, Mireille

doi:10.1038/sj.ejhg.5201478

Cited by 42 publications

(23 citation statements)

References 35 publications

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“…2A). The use of alternative cryptic splice sites could possibly lead to frame-restoring transcripts, resulting in a mixture of aberrantly and correctly spliced transcripts [Lohmann and Gallie, 2004;Tuffery-Giraud et al, 2005], which may explain the reduced disease severity observed; however, why this would be the case in some family members and not in others, remains unclear.…”

Section: Discussionmentioning

confidence: 90%

Genotype–phenotype correlations in hereditary familial retinoblastoma

et al. 2007

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We studied 50 unrelated pedigrees with a family history of retinoblastoma (Rb) (165 carriers of a RB1 mutation) to delineate the spectrum of RB1 germline mutations in familial Rb and to identify genotype-phenotype correlations as well as putative modifiers. Patients were followed at Institut Curie and they were examined by an ophthalmologist, a pediatrician, and a geneticist. All cases of familial Rb were determined via genetic counseling. Clinical features included disease status, laterality, age at diagnosis, mutation type, follow-up, and disease-eye ratio (DER). To eliminate mosaic cases, first-generation carriers displaying low-penetrance (LP) Rb were excluded from the analysis. Complete penetrance was the rule for nonsense and frameshift mutations (25 families) and high penetrance was observed for large rearrangements (eight families). Promoter (two families) and missense (two families) mutations displayed heterogeneous phenotypes and LP. Variable penetrance was observed for splice abnormalities (13 families) and was explained by in/out of frame mutations or respect of functional domains. Surprisingly, two families with the LP g.45867G>T/IVS6+1G>T mutation presented data that conflicted with the data reported in previous publications, as unaffected carriers had paternally inherited mutant alleles. Moreover, RNA analyses suggested that the lack of penetrance in unaffected carriers could be explained by an increase in expression levels of the wild-type allele. This observation prompted us to define a new class "3" of LP alleles. We believe this is the first large-scale study of familial Rb with a high level of homogeneity in the clinical and genetic analysis of patients and their relatives, thereby allowing for reliable intrafamilial genotype-phenotype correlations. Our analysis suggests in some cases the influence of modifier factors probably involved in mRNA level regulation and/or pRB pathway regulation.

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Section: Discussionmentioning

confidence: 90%

Genotype–phenotype correlations in hereditary familial retinoblastoma

et al. 2007

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“…Although insufficient tissue was available from the clinical biopsy for qRT-PCR studies, mRNA sequencing showed no evidence of significant amounts of a second mRNA species, such as may be seen with stop codon-encoding point mutations that induce exon skipping via alteration of ESE elements. 24 This raises the possibility that the premature stop codon signal may be subject to ribosomal readthrough, which is sequence context dependent. 25 However, readthrough does not appear to correlate well with phenotype in DMD patients, 26 and in only a single case has readthrough been implicated in ameliorating a disease phenotype.…”

Section: Discussionmentioning

confidence: 99%

DMD pseudoexon mutations: splicing efficiency, phenotype, and potential therapy

Gurvich

Tuohy

Howard

et al. 2007

Annals of Neurology

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Objective: The degenerative muscle diseases Duchenne (DMD) and Becker muscular dystrophy result from mutations in the DMD gene, which encodes the dystrophin protein. Recent improvements in mutational analysis techniques have resulted in the increasing identification of deep intronic point mutations, which alter splicing such that intronic sequences are included in the messenger RNA as "pseudoexons." We sought to test the hypothesis that the clinical phenotype correlates with splicing efficiency of these mutations, and to test the feasibility of antisense oligonucleotide (AON)-mediated pseudoexon skipping. Methods: We identified three pseudoexon insertion mutations in dystrophinopathy patients, two of whom had tissue available for further analysis. For these two out-of-frame pseudoexon mutations (one associated with Becker muscular dystrophy and one with DMD), mutation-induced splicing was tested by quantitative reverse transcription polymerase chain reaction; pseudoexon skipping was tested using AONs composed of 2Ј-O-methyl-modified bases on a phosphorothioate backbone to treat cultured primary myoblasts. Results: Variable amounts of pseudoexon inclusion correlates with the severity of the dystrophinopathy phenotype in these two patients. AON treatment directed at the pseudoexon results in the expression of full-length dystrophin in a DMD myoblast line. Interpretation: Both DMD and Becker muscular dystrophy can result from out-of-frame pseudoexons, with the difference in phenotype being due to variable efficiency of the newly generated splicing signal. AON-mediated pseudoexon skipping therapy is a viable approach to these patients and would be predicted to result in increased expression of wild-type dystrophin protein.

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“…27 Another group of patients has less than 20% dystrophin expression and they display intermediate phenotype. 3,6,9,26 The mechanism(s) underlying the reduced clinical severity in these patients are not completely understood. Several hypotheses have been suggested including epigenetic, nutritional, and environmental factors, and a palliative effect of low-level dystrophin expression.…”

Section: Discussionmentioning

confidence: 99%

Preservation of Muscle Force in Mdx3cv Mice Correlates with Low-Level Expression of a Near Full-Length Dystrophin Protein

Yue

Duan

2008

The American Journal of Pathology

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The complete absence of dystrophin causes Duchenne muscular dystrophy. Its restoration by greater than 20% is needed to reduce muscle pathology and improve muscle force. Dystrophin levels lower than 20% are considered therapeutically irrelevant but are associated with a less severe phenotype in certain Becker muscular dystrophy patients. To understand the role of low-level dystrophin expression, we compared muscle force and pathology in mdx3cv and mdx4cv mice. Dystrophin was eliminated in mdx4cv mouse muscle but was expressed in mdx3cv mice as a near full-length protein at ϳ5% of normal levels. Consistent with previous reports, we found dystrophic muscle pathology in both mouse strains. Surprisingly, mdx3cv extensor digitorium longus muscle showed significantly higher tetanic force and was also more resistant to eccentric contraction-induced injury than mdx4cv extensor digitorium longus muscle. Furthermore, mdx3cv mice had stronger forelimb grip strength than mdx4cv mice. Immunostaining revealed utrophin up-regulation in both mouse strains. The dystrophin-associated glycoprotein complex was also restored in the sarcolemma in both strains although at levels lower than those in normal mice. Our results suggest that subtherapeutic expression levels of near full-length, membrane-bound dystrophin, possibly in conjunction with up-regulated utrophin levels, may help maintain minimal muscle force but not arrest muscle degeneration or necrosis. Our findings provide valuable insight toward understanding delayed clinical onset and/or slow disease progression in certain Becker muscular dystrophy patients. (Am J

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Mutation spectrum leading to an attenuated phenotype in dystrophinopathies

Cited by 42 publications

References 35 publications

Genotype–phenotype correlations in hereditary familial retinoblastoma

Genotype–phenotype correlations in hereditary familial retinoblastoma

DMD pseudoexon mutations: splicing efficiency, phenotype, and potential therapy

Preservation of Muscle Force in Mdx3cv Mice Correlates with Low-Level Expression of a Near Full-Length Dystrophin Protein

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