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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among the diverse family of collagens, the widely expressed microfibrillar type VI collagen is believed to play a role in bridging cells with the extracellular matrix. Several observations imply substrate properties for cell attachment as well as association with major collagen fibers. Previously, we have established genetic linkage between the genes encoding the three constituent alpha-chains of type VI collagen and Bethlem myopathy. A distinctive feature of this autosomal dominant disorder consists of contractures of multiple joints in addition to generalized muscular weakness and wasting. Nine kindreds show genetic linkage to the COL6A1-COL6A2 cluster on chromosome 21q22.3 (refs 3,4; manuscript submitted) whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3 (ref. 5). Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other kindreds. Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser. Analogous to the putative perturbation of the anchoring function of the dystrophin-associated complex in congenital muscular dystrophy with mutations in the alpha 2-subunit of laminin, our observations suggest a similar mechanism in Bethlem myopathy.
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PMID:Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures. 878 32

Bethlem myopathy is a mild neuromuscular disorder with proximal muscular weakness and early flexion contractures. It is an autosomal dominant disease due to mutations in type VI collagen genes. We found a T-->C substitution at the +2 position of COL6A1 intron 14 in a family, leading to skipping of exon 14 and an in-frame deletion of 18 amino acids in the triple-helical domain of the alpha1(VI) collagen chain. The deletion included a cysteine residue believed to be involved in the assembly of type VI collagen dimers intracellularly, prior to the protein secretion. Analysis of the affected fibroblasts showed that the shortened alpha1(VI) collagen chains were synthesized but not secreted by the cells and that the amount of type VI collagen microfibrils deposited by the cells was reduced. The results suggest that the clinical phenotype is due to a reduction in the level of type VI collagen in the extracellular matrix.
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PMID:A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the alpha1(VI) collagen chain in an italian family affected by bethlem myopathy. 1032 67

Bethlem myopathy is an early-onset benign myopathy characterized by proximal muscular weakness and multiple flexion contractures. It is a dominantly inherited disorder associated with mutations in the three COL6 genes encoding type VI collagen. We detected a g-->a substitution at +1 position of COL6A1 intron 3 in a four-generation Italian family affected by a mild form of Bethlem myopathy. The mutation results in the activation of a cryptic splice donor site at the 3' end of exon 3, leading to the loss of 66 nucleotides and an "in-frame" deletion of 22 amino acids in the NH2-domain. Molecular analysis on fibroblasts of the propositus showed that the mutated mRNA was present and stable, but the mutated protein could not be detected. Western blot and immunofluorescence analyses showed a decreased level of collagen VI synthesis and deposition in fibroblasts of the propositus. Together, the results suggest that the mutated protein was highly unstable and rapidly degraded, and that the mild phenotype was caused by a reduced amount of normal collagen VI microfibrils. In addition, we demonstrated that lymphocytes can be used for the first mutation screening analysis of patients with Bethlem myopathy.
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PMID:Novel COL6A1 splicing mutation in a family affected by mild Bethlem myopathy. 1193 68

We report clinical and muscle magnetic resonance imaging (MRI) findings in three individuals (aged 6, 26 and 73 years) from a three-generation family with Bethlem myopathy, confirmed by molecular genetic analysis which showed an exon skipping mutation in the COL6A1 gene. The clinical severity ranged from mild proximal weakness and distal laxity in the younger patients, to inability to stand or walk and severe contractures in the 76-year-old grandmother. The pattern of muscle involvement showed variable severity in parallel with the severity of motor function impairment. Although there was a marked variability in the severity of the MRI findings, it was possible to recognize a specific pattern of muscle involvement in all three patients. This consisted of involvement of the peripheral region of the vastus lateralis and hamstrings muscles with relative sparing of their central part. This was best appreciated in the third decade of life, but could also be identified both in the younger patient with minimal MRI changes and in the oldest patient, despite her more severe and diffuse muscle involvement. This report suggests that muscle MRI could be used as an additional tool to establish the pattern and the degree of muscle involvement in patients with Bethlem myopathy. Further studies in a larger cohort are needed to evaluate the specificity of these findings.
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PMID:Muscle MRI findings in a three-generation family affected by Bethlem myopathy. 1240 55

Recessive mutations in two of the three collagen VI genes, COL6A2 and COL6A3, have recently been shown to cause Ullrich congenital muscular dystrophy (UCMD), a frequently severe disorder characterized by congenital muscle weakness with joint contractures and coexisting distal joint hyperlaxity. Dominant mutations in all three collagen VI genes had previously been associated with the considerably milder Bethlem myopathy. Here we report that a de novo heterozygous deletion of the COL6A1 gene can also result in a severe phenotype of classical UCMD precluding ambulation. The internal gene deletion occurs near a minisatellite DNA sequence in intron 8 that removes 1.1 kb of genomic DNA encompassing exons 9 and 10. The resulting mutant chain contains a 33-amino acid deletion near the amino-terminus of the triple-helical domain but preserves a unique cysteine in the triple-helical domain important for dimer formation prior to secretion. Thus, dimer formation and secretion of abnormal tetramers can occur and exert a strong dominant negative effect on microfibrillar assembly, leading to a loss of normal localization of collagen VI in the basement membrane surrounding muscle fibers. Consistent with this mechanism was our analysis of a patient with a much milder phenotype, in whom we identified a previously described Bethlem myopathy heterozygous in-frame deletion of 18 amino acids somewhat downstream in the triple-helical domain, a result of exon 14 skipping in the COL6A1 gene. This deletion removes the crucial cysteine, so that dimer formation cannot occur and the abnormal molecule is not secreted, preventing the strong dominant negative effect. Our studies provide a biochemical insight into genotype-phenotype correlations in this group of disorders and establish that UCMD can be caused by dominantly acting mutations.
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PMID:New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. 1284 Jul 83

Ullrich's congenital muscular dystrophy (UCMD) is an autosomal recessive myopathy characterised by neonatal muscle weakness, proximal joint contractures and distal hyperlaxity. Mutations in the COL6A1, COL6A2 (21 q22.3) and COL6A3 (2 q37) genes, encoding the alpha 1, alpha 2 and alpha 3 chains of collagen VI, respectively, have been recently identified as responsible for UCMD in a total of 9 families. We investigated in detail the clinical and morphological phenotype of 15 UCMD patients from 11 consanguineous families showing potential linkage either to 21 q22.3 (6 families) or to 2 q37 (5 families). Collagen VI deficiency was confirmed on muscle biopsies or skin fibroblasts in 8 families. Although all patients shared a common phenotype, a great variability in severity was observed. Collagen VI deficiency in muscle or cultured fibroblasts was complete in the severe cases and partial in the milder ones, which suggests a correlation between the degree of collagen VI deficiency and the clinical severity in UCMD. No significant phenotypical differences were found between the families linked to each of the 2 loci, which confirms UCMD as a unique entity with underlying genetic heterogeneity.
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PMID:Collagen VI status and clinical severity in Ullrich congenital muscular dystrophy: phenotype analysis of 11 families linked to the COL6 loci. 1512 9

Mutations in the three collagen VI genes COL6A1, COL6A2 and COL6A3 cause Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). UCMD, a severe disorder characterized by congenital muscle weakness, proximal joint contractures and marked distal joint hyperextensibility, has been considered a recessive condition, and homozygous or compound heterozygous mutations have been defined in COL6A2 and COL6A3. In contrast, the milder disorder Bethlem myopathy shows clear dominant inheritance and is caused by heterozygous mutations in COL6A1, COL6A2 and COL6A3. This model, where dominant mutations cause mild Bethlem myopathy and recessive mutations cause severe UCMD was recently challenged when a patient with UCMD was shown to have a heterozygous in-frame deletion in COL6A1. We have studied five patients with a clinical diagnosis of UCMD. Three patients had heterozygous in-frame deletions in the N-terminal region of the triple helical domain, one in the alpha1(VI) chain, one in alpha2(VI) and one in alpha3(VI). Collagen VI protein biosynthesis and assembly studies showed that these mutations act in a dominant negative fashion and result in severe collagen VI matrix deficiencies. One patient had recessive amino acid changes in the C2 subdomain of alpha2(VI), which prevented collagen VI assembly. No collagen VI mutations were found in the fifth patient. These data demonstrate that rather than being a rare cause of UCMD, dominant mutations are common in UCMD, now accounting for four of the 14 published cases. Mutation detection in this disorder remains critical for accurate genetic counseling of patients and their families.
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PMID:Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. 1556 6

Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), two conditions which were previously believed to be completely separate entities. BM is a relatively mild dominantly inherited disorder characterised by proximal weakness and distal joint contractures. UCMD was originally described as an autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity. Here we review the clinical phenotypes of BM and UCMD and their diagnosis and management, and provide an overview of the current knowledge of the pathogenesis of collagen VI related disorders.
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PMID:Collagen VI related muscle disorders. 1614 Oct 2

Collagenopathies with collagen VI mutations include Ullrich congenital muscular dystrophy (Ullrich's disease) and Bethlem myopathy. Patients with Ullrich's disease have generalized muscle weakness, multiple contractures of the proximal joints and hyperextensibility of the distal joints. Bethlem myopathy is characterized by the combination of proximal muscle weakness and contractures of finger, elbow, and ankle joints. We found for the first time a deficiency of collagen VI in Ullrich's disease. Furthermore, we found an abnormality of cell adhesion and abnormal regeneration or maturation in Ullrich's disease. Mutations in the genes COL6A1, COL6A2, COL6A3 are associated with Ullrich's disease and Bethlem myopathy. Bethlem myopathy is inherited in an autosomal dominant manner and Ullrich's disease usually in an autosomal recessive manner. Recently, de novo dominant mutations are reported in Ullrich's disease. We evaluated the role of nonsense-mediated mRNA decay (NMD) in Ullrich's disease that has a frameshift mutation with a premature termination codon in the COL6A2 gene causing the loss of collagen VI. The pharmacological block of NMD caused upregulation of the mutant collagen VI and partially functional extracellular matrix formation. Our results suggest that NMD inhibitors can be used as a therapeutic tool to rescue some human genetic diseases exacerbated by NMD.
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PMID:[Collagenopathy (Ullrich congenital muscular dystrophy, Bethlem myopathy)]. 1644 67

Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), two related conditions of differing severity. BM is a relatively mild dominantly inherited disorder characterized by proximal weakness and distal joint contractures. UCMD was originally regarded as an exclusively autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity. We and others have subsequently modified this model when we described UCMD patients with heterozygous in-frame deletions acting in a dominant-negative way. Here we report 10 unrelated patients with a UCMD clinical phenotype and de novo dominant negative heterozygous splice mutations in COL6A1, COL6A2, and COL6A3 and contrast our findings with four UCMD patients with recessively acting splice mutations and two BM patients with heterozygous splice mutations. We find that the location of the skipped exon relative to the molecular structure of the collagen chain strongly correlates with the clinical phenotype. Analysis by immunohistochemical staining of muscle biopsies and dermal fibroblast cultures, as well as immunoprecipitation to study protein biosynthesis and assembly, suggests different mechanisms each for exon skipping mutations underlying dominant UCMD, dominant BM, and recessive UCMD. We provide further evidence that de novo dominant mutations in severe UCMD occur relatively frequently in all three collagen VI chains and offer biochemical insight into genotype-phenotype correlations within the collagen VI-related disorders by showing that severity of the phenotype depends on the ability of mutant chains to be incorporated in the multimeric structure of collagen VI.
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PMID:Exon skipping mutations in collagen VI are common and are predictive for severity and inheritance. 1836 90


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