Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions

Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.Peer reviewe

Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions

Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance

Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to <i>FAM111B </i>mutations

BACKGROUND: Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients. METHODS: Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected. RESULTS: Key features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes. CONCLUSIONS: HFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder

Immune Response and Mitochondrial Metabolism Are Commonly Deregulated in DMD and Aging Skeletal Muscle

Duchenne Muscular Dystrophy (DMD) is a complex process involving multiple pathways downstream of the primary genetic insult leading to fatal muscle degeneration. Aging muscle is a multifactorial neuromuscular process characterized by impaired muscle regeneration leading to progressive atrophy. We hypothesized that these chronic atrophying situations may share specific myogenic adaptative responses at transcriptional level according to tissue remodeling. Muscle biopsies from four young DMD and four AGED subjects were referred to a group of seven muscle biopsies from young subjects without any neuromuscular disorder and explored through a dedicated expression microarray. We identified 528 differentially expressed genes (out of 2,745 analyzed), of which 328 could be validated by an exhaustive meta-analysis of public microarray datasets referring to DMD and Aging in skeletal muscle. Among the 328 validated co-expressed genes, 50% had the same expression profile in both groups and corresponded to immune/fibrosis responses and mitochondrial metabolism. Generalizing these observed meta-signatures with large compendia of public datasets reinforced our results as they could be also identified in other pathological processes and in diverse physiological conditions. Focusing on the common gene signatures in these two atrophying conditions, we observed enrichment in motifs for candidate transcription factors that may coordinate either the immune/fibrosis responses (ETS1, IRF1, NF1) or the mitochondrial metabolism (ESRRA). Deregulation in their expression could be responsible, at least in part, for the same transcriptome changes initiating the chronic muscle atrophy. This study suggests that distinct pathophysiological processes may share common gene responses and pathways related to specific transcription factors

Meta-analysis of muscle transcriptome data using the MADMuscle database reveals biologically relevant gene patterns

<p>Abstract</p> <p>Background</p> <p>DNA microarray technology has had a great impact on muscle research and microarray gene expression data has been widely used to identify gene signatures characteristic of the studied conditions. With the rapid accumulation of muscle microarray data, it is of great interest to understand how to compare and combine data across multiple studies. Meta-analysis of transcriptome data is a valuable method to achieve it. It enables to highlight conserved gene signatures between multiple independent studies. However, using it is made difficult by the diversity of the available data: different microarray platforms, different gene nomenclature, different species studied, etc.</p> <p>Description</p> <p>We have developed a system tool dedicated to muscle transcriptome data. This system comprises a collection of microarray data as well as a query tool. This latter allows the user to extract similar clusters of co-expressed genes from the database, using an input gene list. Common and relevant gene signatures can thus be searched more easily. The dedicated database consists in a large compendium of public data (more than 500 data sets) related to muscle (skeletal and heart). These studies included seven different animal species from invertebrates (<it>Drosophila melanogaster, Caenorhabditis elegans</it>) and vertebrates (<it>Homo sapiens, Mus musculus, Rattus norvegicus, Canis familiaris, Gallus gallus</it>). After a renormalization step, clusters of co-expressed genes were identified in each dataset. The lists of co-expressed genes were annotated using a unified re-annotation procedure. These gene lists were compared to find significant overlaps between studies.</p> <p>Conclusions</p> <p>Applied to this large compendium of data sets, meta-analyses demonstrated that conserved patterns between species could be identified. Focusing on a specific pathology (Duchenne Muscular Dystrophy) we validated results across independent studies and revealed robust biomarkers and new pathways of interest. The meta-analyses performed with MADMuscle show the usefulness of this approach. Our method can be applied to all public transcriptome data.</p

Additions-1,4 d'organometalliques sur des esters alpha,beta-insatures: synthese d'alkylsilylacetals de cetenes et d'esters. Dedoublement enzymatique de gamma-alkoxyesters

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : T 83259 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Mutation du gène codant la protéine 0 responsable d'un phénotype clinique et électrophysiologique de neuropathie par hypersensibilité à la pression

La neuropathie par hypersensibilité à la pression est classiquement décrite associée à une délétion ou à des mutations du gène de la PMP22. Les mutations du gène de la P0 sont responsables de phénotypes variés allant de l'hypomyélinisation congénitale à la maladie de Charcot Marie Tooth. Nous décrivons pour la première fois, dans trois familles de l'Ouest, un phénotype clinique d'HNPP associé à une mutation non-sens du codon 116 du gène de la protéine 0 responsable d'une protéine tronquée dans son domaine extra-cellulaire. Ce phénotype est caractérisé par son évolution secondaire vers une neuropathie longueur dépendante, son tableau démyélinisant et axonal précoce à l'électromyographie. Nous discutons les rôles de la P0 au sein de la myéline, les corrélations génotypes-phénoypes dans les neuropathies héréditaires, l'intégration de ce nouveau phénotype parmi les neuropathies héréditaires. Ce nouveau phénotype étudié représente une nouvelle entité dans le spectre clinique des mutations P0.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF