Fibronectin receptor reduction in skin and fibroblasts of patients with Ullrich's disease

Hu, Jing; Higuchi, Itsuro; Shiraishi, Tadafumi; Suehara, Masahito; Niiyama, Takahito; Horikiri, Takashi; Uchida, Youhei; Saito, Akiko; Osame, Mitsuhiro

doi:10.1002/mus.10250

Cited by 14 publications

(8 citation statements)

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“…Ten possible candidate genes were considered on the basis of the following criteria: either i) their direct interaction with collagen VI, as in the case of HSPG2 [13], ITGA1, ITGA2, ITGB1 [14], DNC and BGN [15]; ii) their secondary involvement in collagen VI-deficient tissues, as in NG2-proteoglycan [16,17], ITGA5 and ITGA7 [18,19], or iii) their mutations causing an overlapping phenotype with collagen VI-related myopathies, as in TNXB [20]. COL6A5 (COL29A1) and COL6A6, which are expressed in skeletal muscle, were also included since collagen VI alpha1-deficient mice do not express collagen VI alpha 5 or alpha 6 chains [21].…”

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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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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“…In our previous study, we found a marked reduction of fibronectin receptors in the skin and cultured fibroblasts of two patients with Ullrich's disease with collagen VI deficiency. We speculated that collagen VI deficiency may lead to a reduction of fibronectin receptors and that an abnormality of cell adhesion may be involved in the pathogenesis of Ullrich's disease 17. Recently, we evaluated the role of nonsense‐mediated mRNA decay (NMD) in Ullrich's disease and found that the pharmacological block of NMD caused upregulation of the mutant collagen VI, resulting in upregulation of the fibronectin receptor and partially functional ECM formation 34.…”

Section: Discussionmentioning

confidence: 99%

Abnormal expression of proteoglycans in Ullrich's disease with collagen VI deficiency

et al. 2005

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Patients with Ullrich's disease have generalized muscle weakness, multiple contractures of the proximal joints, and hyperextensibility of the distal joints. Recently we found a marked reduction of fibronectin receptors in the skin and cultured fibroblasts of two patients with Ullrich's disease with collagen VI deficiency, and speculated that an abnormality of cell adhesion may be involved in the pathogenesis of the disease. In this study, we investigated the expression of proteoglycans and adhesion molecules in Ullrich's disease and other muscle diseases. We found a reduction of NG2 proteoglycan in the membrane of skeletal muscle but not in the skin in Ullrich's disease. By contrast, we found the upregulation of tenascin C in the extracellular matrix of skeletal muscle in Ullrich's disease. Our findings suggest that abnormal expression of proteoglycans and adhesion molecules may be involved in the pathogenesis of the dystrophic muscle changes in Ullrich's disease. Muscle Nerve, 2006

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“…In some UCMD cases collagen VI is completely absent from skin, while in others it may be only reduced or even look normal [117,118]. There is one report of reduced fibronectin receptor expression in the dermis of a UCMD skin biopsy [119]. Primary fibroblasts can be induced to secrete collagen VI in vitro using ascorbic acid in the medium.…”

Section: Diagnosismentioning

confidence: 97%

Congenital muscular dystrophy: molecular and cellular aspects

Jiménez‐Mallebrera

Brown

Sewry

et al. 2005

CMLS, Cell. Mol. Life Sci.

123

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The congenital muscular dystrophies are a clinically and genetically heterogeneous group of neuromuscular disorders. Each form has a characteristic phenotype, but there is overlap between some entities and their classification is based on a combination of clinical features and the primary or secondary protein defect. Recent studies have identified the genetic basis of a number of congenital muscular dystrophies (11 genes in total) and have recognised a novel pathological mechanism that highlights the importance of the correct posttranslational processing of proteins, in particular alpha-dystroglycan. Diagnosis of these conditions has been aided by the availability of specific antibodies for each protein and a better understanding of the protein changes that accompany each condition. In this review we present the major molecular, clinical and diagnostic aspects of each group of congenital muscular dystrophy with an emphasis in the more recent developments.

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Fibronectin receptor reduction in skin and fibroblasts of patients with Ullrich's disease

Cited by 14 publications

References 35 publications

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

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

Abnormal expression of proteoglycans in Ullrich's disease with collagen VI deficiency

Congenital muscular dystrophy: molecular and cellular aspects

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