Collagen VI Status and Clinical Severity in Ullrich Congenital Muscular Dystrophy: Phenotype Analysis of 11 Families Linked to the<i>COL6</i>Loci

Demir, Ercan; Ferreiro, Ana; Sabatelli, Patrizia; Allamand, V.; Makri, S.; Échenne, B.; Maraldi, M.; Merlini, Luciano; Topaloǧlu, Haluk; Guicheney, Pascale

doi:10.1055/s-2004-815832

Cited by 35 publications

(7 citation statements)

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“…At the protein level, this mutation causes a complete absence of the α1 chain both in patient's cells and medium of cultured skin fibroblasts (P3 in Giusti et al, 2005) and in muscle biopsy (Demir et al, 2004), similar to the Col6a1 −/− mice phenotype (Bonaldo et al, 1998). …”

Section: Resultsmentioning

confidence: 88%

Expression of collagen VI α5 and α6 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis

et al. 2012

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Collagen VI is a major extracellular matrix (ECM) protein with a critical role in maintaining skeletal muscle functional integrity. Mutations in COL6A1, COL6A2 and COL6A3 genes cause Ullrich Congenital Muscular Dystrophy (UCMD), Bethlem Myopathy, and Myosclerosis. Moreover, Col6a1−/− mice and collagen VI deficient zebrafish display a myopathic phenotype. Recently, two additional collagen VI chains were identified in humans, the α5 and α6 chains, however their distribution patterns and functions in human skeletal muscle have not been thoroughly investigated yet. By means of immunofluorescence analysis, the α6 chain was detected in the endomysium and perimysium, while the α5 chain labeling was restricted to the myotendinous junctions. In normal muscle cultures, the α6 chain was present in traces in the ECM, while the α5 chain was not detected. In the absence of ascorbic acid, the α6 chain was mainly accumulated into the cytoplasm of a sub-set of desmin negative cells, likely of interstitial origin, which can be considered myofibroblasts as they expressed α-smooth muscle actin. TGF-β1 treatment, a pro-fibrotic factor which induces trans-differentiation of fibroblasts into myofibroblasts, increased the α6 chain deposition in the extracellular matrix after addition of ascorbic acid. In order to define the involvement of the α6 chain in muscle fibrosis we studied biopsies of patients affected by Duchenne Muscular Dystrophy (DMD). We found that the α6 chain was dramatically up-regulated in fibrotic areas where, in contrast, the α5 chain was undetectable. Our results show a restricted and differential distribution of the novel α6 and α5 chains in skeletal muscle when compared to the widely distributed, homologous α3 chain, suggesting that these new chains may play specific roles in specialized ECM structures. While the α5 chain may have a specialized function in tissue areas subjected to tensile stress, the α6 chain appears implicated in ECM remodeling during muscle fibrosis.

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Section: Resultsmentioning

confidence: 88%

Expression of collagen VI α5 and α6 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis

et al. 2012

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“…(# 10, Family 8), who linked the disease in this family to chromosome 21q22.3 [26]. This patient carries a heterozygous small deletion in exon 28 of the COL6A2 gene (NM_001849, c. 2947_2952del6, p.Asp983_Val984del) inherited from the healthy mother.…”

Section: Resultsmentioning

confidence: 99%

Identification of a deep intronic mutation in the COL6A2 gene by a novel custom oligonucleotide CGH array designed to explore allelic and genetic heterogeneity in collagen VI-related myopathies

et al. 2010

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BackgroundMolecular characterization of collagen-VI related myopathies currently relies on standard sequencing, which yields a detection rate approximating 75-79% in Ullrich congenital muscular dystrophy (UCMD) and 60-65% in Bethlem myopathy (BM) patients as PCR-based techniques tend to miss gross genomic rearrangements as well as copy number variations (CNVs) in both the coding sequence and intronic regions.MethodsWe have designed a custom oligonucleotide CGH array in order to investigate the presence of CNVs in the coding and non-coding regions of COL6A1, A2, A3, A5 and A6 genes and a group of genes functionally related to collagen VI. A cohort of 12 patients with UCMD/BM negative at sequencing analysis and 2 subjects carrying a single COL6 mutation whose clinical phenotype was not explicable by inheritance were selected and the occurrence of allelic and genetic heterogeneity explored.ResultsA deletion within intron 1A of the COL6A2 gene, occurring in compound heterozygosity with a small deletion in exon 28, previously detected by routine sequencing, was identified in a BM patient. RNA studies showed monoallelic transcription of the COL6A2 gene, thus elucidating the functional effect of the intronic deletion. No pathogenic mutations were identified in the remaining analyzed patients, either within COL6A genes, or in genes functionally related to collagen VI.ConclusionsOur custom CGH array may represent a useful complementary diagnostic tool, especially in recessive forms of the disease, when only one mutant allele is detected by standard sequencing. The intronic deletion we identified represents the first example of a pure intronic mutation in COL6A genes.

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“…CMDs present a broad phenotypic variability, ranging from severe and lethal forms to milder types compatible with normal life span. Depending on the genetic defect, it is possible to distinguish four forms of CMDs linked to defects of ECM proteins or of their receptors, two associated with mutations in laminin α2 chain and collagen VI (MDC1A and Ullrich/Bethlem, respectively) and two associated with defects of laminin receptors (dystroglycanopathies and integrin α7 deficient congenital myopathy, respectively) [75,76,77,78,79,80,81,82]. …”

Section: Autophagy In Congenital Muscle Dystrophiesmentioning

confidence: 99%

Autophagy in Skeletal Muscle Homeostasis and in Muscular Dystrophies

Grumati

Bonaldo

2012

Cells

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Skeletal muscles are the agent of motion and one of the most important tissues responsible for the control of metabolism. The maintenance of muscle homeostasis is finely regulated by the balance between catabolic and anabolic process. Macroautophagy (or autophagy) is a catabolic process that provides the degradation of protein aggregation and damaged organelles through the fusion between autophagosomes and lysosomes. Proper regulation of the autophagy flux is fundamental for the homeostasis of skeletal muscles during physiological situations and in response to stress. Defective as well as excessive autophagy is harmful for muscle health and has a pathogenic role in several forms of muscle diseases. This review will focus on the role of autophagy in muscle homeostasis and diseases.

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Collagen VI Status and Clinical Severity in Ullrich Congenital Muscular Dystrophy: Phenotype Analysis of 11 Families Linked to theCOL6Loci

Cited by 35 publications

References 29 publications

Expression of collagen VI α5 and α6 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis

Expression of collagen VI α5 and α6 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis

Identification of a deep intronic mutation in the COL6A2 gene by a novel custom oligonucleotide CGH array designed to explore allelic and genetic heterogeneity in collagen VI-related myopathies

Autophagy in Skeletal Muscle Homeostasis and in Muscular Dystrophies

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