Rabah Ben Yaou

Hospital Universitario Virgen Macarena, Hispalis, Andalusia, Spain

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Publications (48)209.94 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms underlying cell response to mechanical forces are critical for muscle development and functionality. We aim to determine whether mutations of the LMNA gene causing congenital muscular dystrophy impair the ability of muscle precursors to sense tissue stiffness and to respond to mechanical challenge. We found that LMNA-mutated myoblasts (LMNA) embedded in soft matrix did not align along the gel axis whereas control myoblasts did. LMNA myoblasts were unable to tune their cytoskeletal tension to the tissue stiffness as attested by inappropriate cell-matrix adhesion sites and cytoskeletal tension in soft versus rigid substrates or after mechanical challenge. Importantly, in soft 2D and/or static 3D conditions, LMNA myoblasts demonstrated enhanced activation of Yes-Associated Protein (YAP) signaling pathway that was paradoxically reduced after cyclic stretch. SiRNA-mediated downregulation of YAP reduced adhesion and actin stress fibers in LMNA myoblasts. This is the first demonstration that human myoblasts with LMNA mutations have mechanosensing defects through a YAP-dependent pathway. In addition, our data emphasize the crucial role of biophysical attributes of cellular microenvironment to the response of mechanosensing pathways in lamin A/C mutated myoblasts.
    Journal of Cell Science 05/2014; · 5.88 Impact Factor
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    ABSTRACT: Muscle diseases may have various clinical manifestations including muscle weakness, atrophy or hypertrophy and joint contractures. A spectrum of non-muscular manifestations (cardiac, respiratory, cutaneous, central and peripheral nervous system…) may be associated. Few of these features are specific. Limb joint contractures or spine rigidity, when prevailing over muscle weakness in ambulant patients, are of high diagnostic value for diagnosis orientation. Within this context, among several disorders, four groups of diseases should systematically come to mind including the collagen VI-related myopathies, the Emery-Dreifuss muscular dystrophies, the SEPN1 and FHL1 related myopathies. More rarely other genetic or acquired myopathies may present with marked contractures. Diagnostic work-up should include a comprehensive assessment including family history, neurological, cardiologic and respiratory evaluations. Paraclinical investigations should minimally include muscle imaging and electromyography. Muscle and skin biopsies as well as protein and molecular analyses usually help to reach a precise diagnosis. We will first describe the main muscle and neuromuscular junction diseases where contractures are typically a prominent symptom of high diagnostic value for diagnosis orientation. In the following chapters, we will present clues for the diagnostic strategy and the main measures to be taken when, at the end of the diagnostic work-up, no definite muscular disease has been identified.
    Revue Neurologique 09/2013; · 0.51 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. While many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence < 5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately, global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardised patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organisations and industry. This article is protected by copyright. All rights reserved.
    Human Mutation 08/2013; · 5.21 Impact Factor
  • European journal of human genetics: EJHG 08/2013; 21(8):892. · 3.56 Impact Factor
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    ABSTRACT: 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 advance online publication, 9 January 2013; doi:10.1038/ejhg.2012.269.
    European journal of human genetics: EJHG 01/2013; · 3.56 Impact Factor
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    ABSTRACT: Currently in most laboratories, molecular investigations of neuromuscular disorders (NMDs) are based on a differential molecular diagnosis by a complex and time-consuming gene by gene approach guided by a clinical approach. As a consequence, it is estimated that 35–50% of patients remain devoid of a precise molecular diagnosis. On one hand, many causal genes for NMDs are still to be identified but, on the other hand, it becomes evident that the current approaches are not sufficiently powerful and accurate to perform exhaustive screenings even in known genes, and that around 50% of patients without a definite molecular diagnosis carry unidentified mutations in known genes. In the recent years, technological tools have been developed towards performing massive molecular analyses using DNA sequence capture (SC) and next generation sequencing (NGS). In the context of the European project “NMD-Chip” (FP7 Health call), we have taken advantage of these technologies to develop specific custom SC DNA arrays to explore via NGS, known and candidate genes for NMDs. A custom in-solution DNA SC library has been designed. It includes 820 genes: 50 are known to be involved in common muscular dystrophies or myopathies (Duchenne/Becker, limb girdle, congenital), the others are candidate genes for those disorders, selected from experimental and published data. To validate this DNA chip, we have selected 20 patient DNAs: five with one known mutation, including point mutations and large rearrangements (1 COL6A2, 1 COL6A1, 1 DOK7, 1 DES, 1 TNXB) and 15 with no molecular diagnosis. We also explored the DNA of three of these patients via Exome sequencing to further compare and validate our custom SC design. The analysis of our data will help to demonstrate the proof of concept of NGS as a robust and accurate approach towards exploring multiple genes in NMD patients.
    Neuromuscular Disorders 10/2012; 22(s 9–10):807–808. · 3.46 Impact Factor
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    ABSTRACT: Dystrophin is a large essential protein of skeletal and heart muscle. It is a filamentous scaffolding protein with numerous binding domains. Mutations in the DMD gene, which encodes dystrophin, mostly result in the deletion of one or several exons and cause Duchenne (DMD) and Becker (BMD) muscular dystrophies. The most common DMD mutations are frameshift mutations resulting in an absence of dystrophin from tissues. In-frame DMD mutations are less frequent and result in a protein with partial wild-type dystrophin function. The aim of this study was to highlight structural and functional modifications of dystrophin caused by in-frame mutations. We developed a dedicated database for dystrophin, the eDystrophin database. It contains 209 different non frame-shifting mutations found in 945 patients from a French cohort and previous studies. Bioinformatics tools provide models of the three-dimensional structure of the protein at deletion sites, making it possible to determine whether the mutated protein retains the typical filamentous structure of dystrophin. An analysis of the structure of mutated dystrophin molecules showed that hybrid repeats were reconstituted at the deletion site in some cases. These hybrid repeats harbored the typical triple coiled-coil structure of native repeats, which may be correlated with better function in muscle cells. This new database focuses on the dystrophin protein and its modification due to in-frame deletions in BMD patients. The observation of hybrid repeat reconstitution in some cases provides insight into phenotype-genotype correlations in dystrophin diseases and possible strategies for gene therapy. The eDystrophin database is freely available: http://edystrophin.genouest.org/.
    Orphanet Journal of Rare Diseases 07/2012; 7:45. · 4.32 Impact Factor
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    ABSTRACT: Duchenne and Becker muscular dystrophies (DMD and BMD) are muscle-wasting diseases caused by mutations in the DMD gene-encoding dystrophin. Usually, out-of-frame deletions give rise to DMD, whereas in-frame deletions result in BMD. BMD patients exhibit a less severe disease because an abnormal but functional dystrophin is produced. This is the rationale for attempts to correct the reading frame by using an exon-skipping strategy. In order to apply this approach to a larger number of patients, a multi-exon skipping strategy of exons 45-55 has been proposed, because it should correct the mRNA reading frame in almost 75% of DMD patients with a deletion. The resulting dystrophin lacks part of the binding site for the neuronal nitric oxide synthase (nNOSμ), which normally binds to spectrin-like repeats 16 and 17 of the dystrophin. Since these domains are encoded by exons 42-45, we investigated the nNOSμ status in muscle biopsies from 12 BMD patients carrying spontaneous deletions spaning exons 45-55. We found a wide spectrum of nNOSμ expression and localization. The strictly cytosolic mislocalization of nNOSμ was associated with the more severe phenotypes. Cytosolic NO production correlated with both hypernitrosylation of the sarcoplasmic reticulum calcium-release-channel ryanodine receptor type-1 (RyR1) and release of calstabin-1, a central hub of Ca(2+) signaling and contraction in muscle. Finally, this study shows that the terminal truncation of the nNOS-binding domain in the 'therapeutic' del45-55 dystrophin is not innocuous, since it can perturb the nNOS-dependent stability of the RyR1/calstabin-1 complex.
    Human Molecular Genetics 05/2012; 21(15):3449-60. · 7.69 Impact Factor
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    ABSTRACT: Mutations in the LMNA gene encoding lamins A/C are responsible for more than ten different disorders called laminopathies which affect various tissues in an isolated (striated muscle, adipose tissue or peripheral nerve) or systemic (premature aging syndromes) fashion. Overlapping phenotypes are also observed. Associated with this wide clinical variability, there is also a large genetic heterogeneity, with 408 different mutations being reported to date. Whereas a few hotspot mutations emerge for some types of laminopathies, relationships between genotypes and phenotypes remain poor for laminopathies affecting the striated muscles. In addition, there is important intrafamilial variability, explained only in a few cases by digenism, thus suggesting an additional contribution from modifier genes. In this regard, a chromosomal region linked to the variability in the age at onset of myopathic symptoms in striated muscle laminopathies has recently been identified. This locus is currently under investigation to identify modifier variants responsible for this variability.
    Biochemical Society Transactions 12/2011; 39(6):1687-92. · 2.59 Impact Factor
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    ABSTRACT: The diagnosis of Emery-Dreifuss muscular dystrophy (EDMD) is suggested by the combination of musculoskeletal weakness and wasting, joint contractures, and cardiac disease. Herein we report a patient in whom an ischemic stroke prompted the diagnosis of EDMD. A mutation in the LMNA gene (c.266G>T, p.Arg89Leu) was found. It had been reported previously exclusively with isolated cardiac disease, thus reinforcing the high phenotypic heterogeneity of laminopathies.
    Muscle & Nerve 10/2011; 44(4):587-9. · 2.31 Impact Factor
  • Neuromuscular Disorders 10/2011; 21(9):672-673. · 3.46 Impact Factor
  • Neuromuscular Disorders 10/2011; 21(9):673. · 3.46 Impact Factor
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    ABSTRACT: Mutation in ZMPSTE24 gene, encoding a major metalloprotease, leads to defective prelamin A processing and causes type B mandibuloacral dysplasia, as well as the lethal neonatal restrictive dermopathy syndrome. Phenotype severity is correlated with the residual enzyme activity of ZMPSTE24 and accumulation of prelamin A. We had previously demonstrated that a complete loss of function in ZMPSTE24 was lethal in the neonatal period, whereas compound heterozygous mutations including one PTC and one missense mutation were associated with type B mandibuloacral dysplasia. In this study, we report a 30-year longitudinal clinical survey of a patient harboring a novel severe and complex phenotype, combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion. A unique homozygous missense ZMPSTE24 mutation (c.281T>C, p.Leu94Pro) was identified and predicted to produce two possible ZMPSTE24 conformations, leading to a partial loss of function. Western blot analysis revealed a major reduction of ZMPSTE24, together with the presence of unprocessed prelamin A and decreased levels of lamin A, in the patient's primary skin fibroblasts. These cells exhibited significant reductions in lifespan associated with major abnormalities of the nuclear shape and structure. This is the first report of MAD presenting with confirmed myopathic abnormalities associated with ZMPSTE24 defects, extending the clinical spectrum of ZMPSTE24 gene mutations. Moreover, our results suggest that defective prelamin A processing affects muscle regeneration and development, thus providing new insights into the disease mechanism of prelamin A-defective associated syndromes in general.
    European journal of human genetics: EJHG 01/2011; 19(6):647-54. · 3.56 Impact Factor
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    ABSTRACT: Lamins A and C, encoded by the LMNA gene, are nuclear proteins expressed in all post-mitotic cells. Together with B-type lamins, they form a meshwork of proteins beneath the inner nuclear membrane, the lamina, in connection with the cytoskeleton. Lamins A/C also interact with chromatin and numerous proteins, including transcription factors. Mutations in LMNA are responsible for more than ten different disorders, commonly called "laminopathies". These diseases affect tissues in a specific (striated muscle, adipose tissue, peripheral nerve) or in a systemic manner (premature ageing syndromes). This wide spectrum of phenotypes is associated to a wide variety of mutations. This large clinical and genetic heterogeneity, unique to the LMNA gene, makes genotype-phenotype relations particularly difficult to establish. However, correlations have been obtained in several cases. Hence, LMNA mutations identified in premature ageing syndromes lead to the accumulation of immature proteins with a toxic effect for cells. Mutations in laminopathies of the adipose tissue mainly localize in the Ig-like domain of the proteins, potentially affecting the interaction with the SREBP-1 transcription factor. In laminopathies of the striated muscles, the mutations are spread throughout the gene. These mutations are thought to induce structural modifications of the proteins, thereby affecting their polymerization into nuclear lamina. Such defect would lead to a mechanical weakness of the nuclear lamina and of the cells, particularly in striated muscles continuously stretching. The exploration of pathophysiological mechanisms of LMNA mutations largely benefits from the numerous mouse models created, which have been widely used to analyze affected molecular pathways and to test putative therapeutic treatments.
    Biologie aujourd'hui. 01/2011; 205(3):147-62.
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    ABSTRACT: Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in LMNA gene encoding lamins A and C. The disease is characterized by early onset joint contractures during childhood associated with humero-peroneal muscular wasting and weakness, and by the development of a cardiac disease in adulthood. Important intra-familial variability characterized by a wide range of age at onset of myopathic symptoms (AOMS) has been recurrently reported, suggesting the contribution of a modifier gene. Our objective was to identify a modifier locus of AOMS in relation with the LMNA mutation. To map the modifier locus, we genotyped 291 microsatellite markers in 59 individuals of a large French family, where 19 patients carrying the same LMNA mutation, exhibited wide range of AOMS. We performed Bayesian Markov Chain Monte Carlo-based joint segregation and linkage methods implemented in the Loki software, and detected a strong linkage signal on chromosome 2 between markers D2S143 and D2S2244 (211 cM) with a Bayes factor of 28.7 (empirical p value = 0.0032). The linked region harbours two main candidate genes, DES and MYL1 encoding desmin and light chain of myosin. Importantly, the impact of the genotype on the phenotype for this locus showed an overdominant effect with AOMS 2 years earlier for the homozygotes of the rare allele and 37 years earlier for the heterozygotes than the homozygotes for the common allele. These results provide important highlights for the natural history and for the physiopathology of Emery-Dreifuss muscular dystrophy.
    Human Genetics 11/2010; 129(2):149-59. · 4.63 Impact Factor
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    ABSTRACT: Bethlem myopathy and Ullrich congenital muscular dystrophy are part of the heterogeneous group of collagen VI-related muscle disorders. They are caused by mutations in collagen VI (ColVI) genes (COL6A1, COL6A2, and COL6A3) while LMNA mutations cause autosomal dominant Emery-Dreifuss muscular dystrophy. A muscular dystrophy pattern and contractures are found in all three conditions, making differential diagnosis difficult especially in young patients when cardiomyopathy is absent. We retrospectively assessed upper and lower limb muscle CT scans in 14 Bethlem/Ullrich patients and 13 Emery-Dreifuss patients with identified mutations. CT was able to differentiate Emery-Dreifuss muscular dystrophy from ColVI-related myopathies in selected thigh muscles and to a lesser extent calves muscles: rectus femoris fatty infiltration was selectively present in Bethlem/Ullrich patients while posterior thigh muscles infiltration was more prominently found in Emery-Dreifuss patients. A more severe fatty infiltration particularly in the leg posterior compartment was found in the Emery-Dreifuss group.
    Neuromuscular Disorders 08/2010; 20(8):517-23. · 3.46 Impact Factor
  • Neuromuscular Disorders - NEUROMUSCULAR DISORD. 01/2010; 20(9):623-624.
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    ABSTRACT: We investigated a large German family (n = 37) with male members who had contractures, rigid spine syndrome, and hypertrophic cardiomyopathy. Muscle weakness or atrophy was not prominent in affected individuals. Muscle biopsy disclosed a myopathic pattern with cytoplasmic bodies. We used microsatellite markers and found linkage to a locus at Xq26-28, a region harboring the FHL1 gene. We sequenced FHL1 and identified a new missense mutation within the third LIM domain that replaces a highly conserved cysteine by an arginine (c.625T>C; p.C209R). Our finding expands the phenotypic spectrum of the recently identified FHL1-associated myopathies and widens the differential diagnosis of Emery–Dreifuss–like syndromes. ANN NEUROL 2010;67:136–140
    Annals of Neurology 12/2009; 67(1):136 - 140. · 11.19 Impact Factor
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    ABSTRACT: Emery-Dreifuss muscular dystrophy (EDMD) is a rare disorder characterized by early joint contractures, muscular dystrophy, and cardiac involvement with conduction defects and arrhythmias. So far, only 35% of EDMD cases are genetically elucidated and associated with EMD or LMNA gene mutations, suggesting the existence of additional major genes. By whole-genome scan, we identified linkage to the Xq26.3 locus containing the FHL1 gene in three informative families belonging to our EMD- and LMNA-negative cohort. Analysis of the FHL1 gene identified seven mutations, in the distal exons of FHL1 in these families, three additional families, and one isolated case, which differently affect the three FHL1 protein isoforms: two missense mutations affecting highly conserved cysteines, one abolishing the termination codon, and four out-of-frame insertions or deletions. The predominant phenotype was characterized by myopathy with scapulo-peroneal and/or axial distribution, as well as joint contractures, and associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families. Heterozygous female carriers were either asymptomatic or had cardiac disease and/or mild myopathy. Interestingly, four of the FHL1-mutated male relatives had isolated cardiac disease, and an overt hypertrophic cardiomyopathy was present in two. Expression and functional studies demonstrated that the FHL1 proteins were severely reduced in all tested patients and that this was associated with a severe delay in myotube formation in the two patients for whom myoblasts were available. In conclusion, FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy.
    The American Journal of Human Genetics 10/2009; 85(3):338-53. · 11.20 Impact Factor
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    ABSTRACT: UMD-DMD France is a knowledgebase developed through a multicenter academic effort to provide an up-to-date resource of curated information covering all identified mutations in patients with a dystrophinopathy. The current release includes 2,411 entries consisting in 2,084 independent mutational events identified in 2,046 male patients and 38 expressing females, which corresponds to an estimated number of 39 people per million with a genetic diagnosis of dystrophinopathy in France. Mutations consist in 1,404 large deletions, 215 large duplications, and 465 small rearrangements, of which 39.8% are nonsense mutations. The reading frame rule holds true for 96% of the DMD patients and 93% of the BMD patients. Quality control relies on the curation by four experts for the DMD gene and related diseases. Data on dystrophin and RNA analysis, phenotypic groups, and transmission are also available. About 24% of the mutations are de novo events. This national centralized resource will contribute to a greater understanding of prevalence of dystrophinopathies in France, and in particular, of the true frequency of BMD, which was found to be almost half (43%) that of DMD. UMD-DMD is a searchable anonymous database that includes numerous newly developed tools, which can benefit to all the scientific community interested in dystrophinopathies. Dedicated functions for genotype-based therapies allowed the prediction of a new multiexon skipping (del 45-53) potentially applicable to 53% of the deleted DMD patients. Finally, such a national database will prove to be useful to implement the international global DMD patients' registries under development.
    Human Mutation 02/2009; 30(6):934-45. · 5.21 Impact Factor

Publication Stats

912 Citations
209.94 Total Impact Points

Institutions

  • 2011
    • Hospital Universitario Virgen Macarena
      Hispalis, Andalusia, Spain
    • Institute of Myology
      Lutetia Parisorum, Île-de-France, France
  • 2009–2010
    • Pierre and Marie Curie University - Paris 6
      • Institut de myologie
      Lutetia Parisorum, Île-de-France, France
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 2005–2008
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      Lutetia Parisorum, Île-de-France, France