Two novel COL6A3 mutations disrupt extracellular matrix formation and lead to myopathy from Ullrich congenital muscular dystrophy and Bethlem myopathy spectrum

Marakhonov, Andrey V.; Tabakov, Vyacheslav; Зернов, Н. В.; Дадали, Е. Л.; Шаркова, И. В.; Skoblov, Mikhail

doi:10.1016/j.gene.2018.06.026

Cited by 17 publications

(18 citation statements)

References 21 publications

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“…COL6A3 works to bind extracellular matrix proteins suggesting an interaction with collagen in organizing matrix components. [27] SERPINE1 functions in tissue repair and regulates plasmin formation, which degrades extracellular matrices that may favor cancer cell invasion [28,29].…”

Section: Plos Onementioning

confidence: 99%

Regulatory effects of Lactobacillus plantarum HY7714 on skin health by improving intestinal condition

et al. 2020

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Despite increasing research on the gut-skin axis, there is a lack of comprehensive studies on the improvement of skin health through the regulation of the intestinal condition in humans. In this study, we investigated the benefits of Lactobacillus plantarum HY7714 (HY7714) consumption on skin health through its modulatory effects on the intestine and ensuing immune responses. HY7714 consumption led to differences in bacterial abundances from phylum to genus level, including increases in Actinobacteria followed by Bifidobacterium and a decrease in Proteobacteria. Additionally, HY7714 significantly ameliorated inflammation by reducing matrix metallopeptidases (MMP-2 and MMP-9), zonulin, and calprotectin in plasma, all of which are related to skin and intestinal permeability. Furthermore, RNA-seq analysis revealed its efficacy at restoring the integrity of the gut barrier by regulating gene expression associated with the extracellular matrix and immunity. This was evident by the upregulation of IGFBP5, SERPINE1, EFEMP1, COL6A3, and SEMA3B and downregulation of MT2A, MT1E, MT1X, MT1G, and MT1F between TNFα and TNFα plus HY7714 treated Caco-2 cells. These results propose the potential mechanistic role of HY7714 on skin health by the regulation of the gut condition. OPEN ACCESS Citation: Nam B, Kim SA, Park SD, Kim HJ, Kim JS, Bae CH, et al. (2020) Regulatory effects of Lactobacillus plantarum HY7714 on skin health by improving intestinal condition. PLoS ONE 15(4): e0231268. https://doi.org/10.

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Section: Plos Onementioning

confidence: 99%

Regulatory effects of Lactobacillus plantarum HY7714 on skin health by improving intestinal condition

et al. 2020

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“…3A) and thereby gives clues for pathomechanisms. The mutations R1660C, D1674N, G1679E and L1726R were selected from literature or from the Leiden Open Variation Database (LOVD https://www.lovd.nl/), using the criteria that they were i) likely pathogenic and/or ii) had supporting data from patient material indicating pathogenicity (25)(26)(27)(28). The mutations cover a spectrum of prototypic locations within an VWA domain.…”

Section: The N2 Vwa Domain Harbouring Bm and Ucmd Mutations Exhibit Dmentioning

confidence: 99%

“…Especially the lack of structural information makes it difficult to predict the consequences of changes in the amino acid sequence for the structure and thereby the function of the protein. The N2 domain of the α3 chain, on the boundary between the triple helical core region and the extended array of N-terminal VWA domains, harbours several missense mutations that have been proposed to be pathogenic or likely pathogenic (25)(26)(27)(28). Notably, the α3 N2 domain has previously undergone crystallography attempts (29) which were unsuccessful.…”

Section: The Location Of Point Mutations In the Structure Of The N2 Vmentioning

confidence: 99%

“…Further, such information will help in studies aimed at revealing the pathomechanisms underpinning collagen VI myopathies. Although mutations which affect the triple helix are the most common (24), several mutations in the N-and C-terminal VWA domains have also been shown to cause disease (7) and especially the N2 VWA domain of the α3 chain harbours several pathogenic point mutations (25)(26)(27)(28). Here, we determine the structure of the collagen α3 N2 domain by X-ray crystallography and study the effects of introducing BM and UCMD patient mutations (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Structure of a collagen VI α3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations

Solomon-Degefa

Gebauer

Jeffries

et al. 2020

Journal of Biological Chemistry

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Collagen VI is a ubiquitous heterotrimeric protein of the extracellular matrix (ECM) that plays an essential role in the proper maintenance of skeletal muscle. Mutations in collagen VI lead to a spectrum of congenital myopathies, from the mild Bethlem Myopathy to the severe Ullrich Congenital Muscular Dystrophy. Collagen VI contains only a short triple helix and consists primarily of von Willebrand Factor type A (VWA) domains, protein-protein interaction modules found in a range of ECM proteins. Disease causing mutations occur commonly in the VWA domains, and the second VWA domain of the α3 chain, the N2 domain, harbors several such mutations. Here, we investigate structure-function relationships of the N2 mutations to shed light on their possible myopathy mechanisms. We determined the X-ray crystal structure of N2, combined with monitoring secretion efficiency in cell culture of selected N2 single domain mutants, finding that mutations located within the central core of the domain severely affect secretion efficiency. In longer α3 chain constructs, spanning N6-N3, small-angle X-ray scattering demonstrates that the tandem VWA array has a modular architecture and samples multiple conformations in solution. Single particle EM confirmed the presence of multiple conformations. Structural adaptability appears intrinsic to the VWA domain region of collagen VI α3 and has implications for binding interactions and modulating stiffness within the ECM.

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“…Primary fibroblasts were obtained from forearm skin biopsy as previously described by Marakhonov et al [20]. The total RNA was extracted from fibroblasts by the standard Trizol-based method.…”

Section: Case Presentationmentioning

confidence: 99%

CTNS mRNA molecular analysis revealed a novel mutation in a child with infantile nephropathic cystinosis: a case report

et al. 2019

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Background: Cystinosis is an autosomal recessive lysosomal storage disorder characterized by accumulation of cystine in lysosomes throughout the body. Cystinosis is caused by mutations in the CTNS gene that encodes the lysosomal cystine carrier protein cystinosin. CTNS mutations result in either complete absence or reduced cystine transporting function of the protein. The diagnosis of nephropathic cystinosis is generally based on measuring leukocyte cystine level, demonstration of corneal cystine crystals by the slit lamp examination and confirmed by genetic analysis of the CTNS gene. Case presentation: A boy born to consanguineous Caucasian parents had the characteristic clinical features of the infantile nephropathic cystinosis including renal Fanconi syndrome (polydipsia/polyuria, metabolic acidosis, hypokalemia, hypophosphatemia, low molecular weight proteinuria, glycosuria, cystine crystals in the cornea) and elevated WBC cystine levels. Initially we performed RFLP analysis of the common in the Northern European population 57-kb deletion of proband's DNA, then a direct Sanger sequencing which revealed no mutations in the coding part of the CTNS gene. To confirm the diagnosis we performed RT-PCR analysis of total RNA obtained from patient-derived fibroblasts in combination with cDNA sequencing. This revealed the skipping of exon 4 and exon 5 in the CTNS in our patient. Therefore, we detected a novel 9-kb homozygous deletion in the CTNS gene at genomic DNA level, spanning region from intron 3 to intron 5. In order to identify the inheritance pattern of the deletion we analyzed DNA of proband's mother and father. Both parents were found to be heterozygous carriers of the CTNS mutation. Conclusions: Analysis of CTNS gene transcript allowed to identify a large homozygous deletion in the patient with infantile nephropathic cystinosis. Mutational detection at RNA level may be an efficient tool to establish the genetic defect in some cystinosis patients.

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Two novel COL6A3 mutations disrupt extracellular matrix formation and lead to myopathy from Ullrich congenital muscular dystrophy and Bethlem myopathy spectrum

Cited by 17 publications

References 21 publications

Regulatory effects of Lactobacillus plantarum HY7714 on skin health by improving intestinal condition

Regulatory effects of Lactobacillus plantarum HY7714 on skin health by improving intestinal condition

Structure of a collagen VI α3 chain VWA domain array: adaptability and functional implications of myopathy causing mutations

CTNS mRNA molecular analysis revealed a novel mutation in a child with infantile nephropathic cystinosis: a case report

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