Autosomal recessive myosclerosis myopathy is a collagen VI disorder

Merlini, Luciano; Martoni, E.; Grumati, Paolo; Sabatelli, Patrizia; Squarzoni, Stefano; Urciuolo, Anna; Ferlini, Alessandra; Gualandi, Francesca; Bonaldo, Paolo

doi:10.1212/01.wnl.0000327611.01687.5e

Cited by 111 publications

(110 citation statements)

References 32 publications

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“…Different truncating mutations of the C-terminal part of the α2(VI) chain were previously reported in some patients affected by either UCMD or myosclerosis myopathy (Zhang et al, 2002;Merlini et al, 2008).…”

Section: Discussionmentioning

confidence: 95%

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Identification and characterization of novel collagen VI non-canonical splicing mutations causing ullrich congenital muscular dystrophy

Martoni

Urciuolo

Sabatelli³

et al. 2009

Hum. Mutat.

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Splicing mutations occurring outside the invariant GT and AG dinucleotides are frequent in disease genes and the definition of their pathogenic potential is often challenging. We have identified four patients affected by Ullrich congenital muscular dystrophy and carrying unusual mutations of COL6 genes affecting RNA splicing. In three cases the mutations occurred in the COL6A2 gene and consisted of nucleotide substitutions within the degenerated sequences flanking the canonical dinucleotides. In the fourth case, a genomic deletion occurred which removed the exon8-intron8 junction of the COL6A1 gene. These mutations induced variable splicing phenotypes, consisting of exon skipping, intron retention and cryptic splice site activation/usage. A quantitative RNA assay revealed a reduced level of transcription of the mutated in-frame mRNA originating from a COL6A2 point mutation at intronic position +3. At variance, the transcription level of the mutated in-frame mRNA originating from a genomic deletion which removed the splicing sequences of COL6A1 exon 8 was normal. These findings suggest a different transcriptional efficiency of a regulatory splicing mutation compared to a genomic deletion causing a splicing defect.

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Section: Discussionmentioning

confidence: 95%

“…RT-PCR was performed as previously described (Merlini et al, 2008). Sequence of primers is available upon request.…”

Section: Rna Analysismentioning

confidence: 99%

Identification and characterization of novel collagen VI non-canonical splicing mutations causing ullrich congenital muscular dystrophy

Martoni

Urciuolo

Sabatelli³

et al. 2009

Hum. Mutat.

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“…Interstitial fibroblasts are the major cell type responsible for its deposition, whereas myogenic cells, which contain factors that can influence ColVI secretion, do not express it (Braghetta et al, 2008;Zou et al, 2008). The crucial role of ColVI in skeletal muscle is emphasized by the fact that mutations in the genes encoding ColVI chains have a causative role in several forms of inherited human muscle diseases, including Bethlem myopathy, Ullrich congenital muscular dystrophy (UCMD) and myosclerosis myopathy (Jöbsis et al, 1996;Camacho Vanegas et al, 2001;Merlini et al, 2008). Interestingly, complete ablation of ColVI in Col6a1 −/− mice leads to an early-onset myopathic phenotype that is characterized by structural and functional defects of the diaphragm and other skeletal muscles (Bonaldo et al, 1998).…”

Section: Skeletal Musclementioning

confidence: 99%

Collagen VI at a glance

Cescon

Gattazzo

Chen

et al. 2015

Journal of Cell Science

285

286

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Collagen VI represents a remarkable extracellular matrix molecule, and in the past few years, studies of this molecule have revealed its involvement in a wide range of tissues and pathological conditions. In addition to its complex multi-step pathway of biosynthesis and assembly that leads to the formation of a characteristic and distinctive network of beaded microfilaments in the extracellular matrix, collagen VI exerts several key roles in different tissues. These range from unique biomechanical roles to cytoprotective functions in different cells, including myofibers, chondrocytes, neurons, fibroblasts and cardiomyocytes. Indeed, collagen VI has been shown to exert a surprisingly broad range of cytoprotective effects, which include counteracting apoptosis and oxidative damage, favoring tumor growth and progression, regulating autophagy and cell differentiation, and even contributing to the maintenance of stemness. In this Cell Science at a Glance article and the accompanying poster, we present the current knowledge of collagen VI, and in particular, discuss its relevance in stemness and in preserving the mechanical properties of tissues, as well as its links with human disorders.

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“…In contrast to Bethlem myopathy, UCMD is marked by an early loss of ambulation and a rapid disease progression leading to early death caused by respiratory failure (Maraldi et al, 2009). In addition, two other conditions have been associated with ColVI myopathy: autosomal-dominant limbgirdle muscular dystrophy (LGMD), and autosomal-recessive myosclerosis myopathy (Merlini et al, 2008;Scacheri et al, 2002). Recently, the COL12A1 gene has been shown to be mutated in patients with a Bethlem-myopathy-like phenotype (Hicks et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy

Scotton

Bovolenta

Schwartz

et al. 2016

Journal of Cell Science

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Collagen VI myopathies are genetic disorders caused by mutations in collagen 6 A1, A2 and A3 genes, ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, which is recapitulated by collagen-VI-null (Col6a1 −/− ) mice. Abnormalities in mitochondria and autophagic pathway have been proposed as pathogenic causes of collagen VI myopathies, but the link between collagen VI defects and these metabolic circuits remains unknown. To unravel the expression profiling perturbation in muscles with collagen VI myopathies, we performed a deep RNA profiling in both Col6a1 −/− mice and patients with collagen VI pathology. The interactome map identified common pathways suggesting a previously undetected connection between circadian genes and collagen VI pathology. Intriguingly, Bmal1 −/− (also known as Arntl) mice, a well-characterized model displaying arrhythmic circadian rhythms, showed profound deregulation of the collagen VI pathway and of autophagy-related genes. The involvement of circadian rhythms in collagen VI myopathies is new and links autophagy and mitochondrial abnormalities. It also opens new avenues for therapies of hereditary myopathies to modulate the molecular clock or potential gene-environment interactions that might modify muscle damage pathogenesis.

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Autosomal recessive myosclerosis myopathy is a collagen VI disorder

Cited by 111 publications

References 32 publications

Identification and characterization of novel collagen VI non-canonical splicing mutations causing ullrich congenital muscular dystrophy

Identification and characterization of novel collagen VI non-canonical splicing mutations causing ullrich congenital muscular dystrophy

Collagen VI at a glance

Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy

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