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Clinical and Molecular Spectrum Associated with COL6A3 c.7447A>G p.(Lys2483Glu) Variant : Elucidating its Role in Collagen VI-related Myopathies

Villar-Quiles, Rocío N. ; Donkervoort, Sandra ; De Becdelièvre, Alix ; Gartioux, Corine ; Jobic, Valérie ; Foley, A. Reghan ; McCarty, Riley M. ; Hu, Ying ; Menassa, Rita and Michel, Laurence , et al. (2021) In Journal of Neuromuscular Diseases 8(4). p.633-645
Abstract

Background: Dominant and recessive autosomal pathogenic variants in the three major genes (COL6A1-A2-A3) encoding the extracellular matrix protein collagen VI underlie a group of myopathies ranging from early-onset severe conditions (Ullrich congenital muscular dystrophy) to milder forms maintaining independent ambulation (Bethlem myopathy). Diagnosis is based on the combination of clinical presentation, muscle MRI, muscle biopsy, analysis of collagen VI secretion, and COL6A1-A2-A3 genetic analysis, the interpretation of which can be challenging. Objective: To refine the phenotypical spectrum associated with the frequent COL6A3 missense variant c.7447A>G (p.Lys2483Glu). Methods: We report the clinical and molecular findings in 16... (More)

Background: Dominant and recessive autosomal pathogenic variants in the three major genes (COL6A1-A2-A3) encoding the extracellular matrix protein collagen VI underlie a group of myopathies ranging from early-onset severe conditions (Ullrich congenital muscular dystrophy) to milder forms maintaining independent ambulation (Bethlem myopathy). Diagnosis is based on the combination of clinical presentation, muscle MRI, muscle biopsy, analysis of collagen VI secretion, and COL6A1-A2-A3 genetic analysis, the interpretation of which can be challenging. Objective: To refine the phenotypical spectrum associated with the frequent COL6A3 missense variant c.7447A>G (p.Lys2483Glu). Methods: We report the clinical and molecular findings in 16 patients: 12 patients carrying this variant in compound heterozygosity with another COL6A3 variant, and four homozygous patients. Results: Patients carrying this variant in compound heterozygosity with a truncating COL6A3 variant exhibit a phenotype consistent with COL6-related myopathies (COL6-RM), with joint contractures, proximal weakness and skin abnormalities. All remain ambulant in adulthood and only three have mild respiratory involvement. Most show typical muscle MRI findings. In five patients, reduced collagen VI secretion was observed in skin fibroblasts cultures. All tested parents were unaffected heterozygous carriers. Conversely, two out of four homozygous patients did not present with the classical COL6-RM clinical and imaging findings. Collagen VI immunolabelling on cultured fibroblasts revealed rather normal secretion in one and reduced secretion in another. Muscle biopsy from one homozygous patient showed myofibrillar disorganization and rimmed vacuoles. Conclusions: In light of our results, we postulate that the COL6A3 variant c.7447A>G may act as a modulator of the clinical phenotype. Thus, in patients with a typical COL6-RM phenotype, a second variant must be thoroughly searched for, while for patients with atypical phenotypes further investigations should be conducted to exclude alternative causes. This works expands the clinical and molecular spectrum of COLVI-related myopathies.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
COL6A3, collagen type VI, Collagen VI-related myopathies, congenital muscular dystrophy (CMD), limb-girdle muscular dystrophy (LGMD), muscular MRI, neuromuscular disorders, NGS
in
Journal of Neuromuscular Diseases
volume
8
issue
4
pages
13 pages
publisher
IOS Press
external identifiers
  • pmid:33749658
  • scopus:85112029214
ISSN
2214-3599
DOI
10.3233/JND-200577
language
English
LU publication?
yes
id
9e54c712-d4e4-4cfb-889e-f33c41939210
date added to LUP
2021-09-02 17:02:04
date last changed
2025-01-26 14:42:21
@article{9e54c712-d4e4-4cfb-889e-f33c41939210,
  abstract     = {{<p>Background: Dominant and recessive autosomal pathogenic variants in the three major genes (COL6A1-A2-A3) encoding the extracellular matrix protein collagen VI underlie a group of myopathies ranging from early-onset severe conditions (Ullrich congenital muscular dystrophy) to milder forms maintaining independent ambulation (Bethlem myopathy). Diagnosis is based on the combination of clinical presentation, muscle MRI, muscle biopsy, analysis of collagen VI secretion, and COL6A1-A2-A3 genetic analysis, the interpretation of which can be challenging. Objective: To refine the phenotypical spectrum associated with the frequent COL6A3 missense variant c.7447A&gt;G (p.Lys2483Glu). Methods: We report the clinical and molecular findings in 16 patients: 12 patients carrying this variant in compound heterozygosity with another COL6A3 variant, and four homozygous patients. Results: Patients carrying this variant in compound heterozygosity with a truncating COL6A3 variant exhibit a phenotype consistent with COL6-related myopathies (COL6-RM), with joint contractures, proximal weakness and skin abnormalities. All remain ambulant in adulthood and only three have mild respiratory involvement. Most show typical muscle MRI findings. In five patients, reduced collagen VI secretion was observed in skin fibroblasts cultures. All tested parents were unaffected heterozygous carriers. Conversely, two out of four homozygous patients did not present with the classical COL6-RM clinical and imaging findings. Collagen VI immunolabelling on cultured fibroblasts revealed rather normal secretion in one and reduced secretion in another. Muscle biopsy from one homozygous patient showed myofibrillar disorganization and rimmed vacuoles. Conclusions: In light of our results, we postulate that the COL6A3 variant c.7447A&gt;G may act as a modulator of the clinical phenotype. Thus, in patients with a typical COL6-RM phenotype, a second variant must be thoroughly searched for, while for patients with atypical phenotypes further investigations should be conducted to exclude alternative causes. This works expands the clinical and molecular spectrum of COLVI-related myopathies.</p>}},
  author       = {{Villar-Quiles, Rocío N. and Donkervoort, Sandra and De Becdelièvre, Alix and Gartioux, Corine and Jobic, Valérie and Foley, A. Reghan and McCarty, Riley M. and Hu, Ying and Menassa, Rita and Michel, Laurence and Gousse, Gaelle and Lacour, Arnaud and Petiot, Philippe and Streichenberger, Nathalie and Choumert, Ariane and Declerck, Leá and Urtizberea, J. A. and Sole, Guilhem and Furby, Alain and Cérino, Matthieu and Krahn, Martin and Campana- Salort, Emmanuelle and Ferreiro, Ana and Eymard, Bruno and Bönnemann, Carsten G. and Bharucha-Goebel, Diana and Sumner, Charlotte J. and Connolly, Anne M. and Richard, Pascale and Allamand, Valérie and Métay, Corinne and Stojkovic, Tanya}},
  issn         = {{2214-3599}},
  keywords     = {{COL6A3; collagen type VI; Collagen VI-related myopathies; congenital muscular dystrophy (CMD); limb-girdle muscular dystrophy (LGMD); muscular MRI; neuromuscular disorders; NGS}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{633--645}},
  publisher    = {{IOS Press}},
  series       = {{Journal of Neuromuscular Diseases}},
  title        = {{Clinical and Molecular Spectrum Associated with COL6A3 c.7447A>G p.(Lys2483Glu) Variant : Elucidating its Role in Collagen VI-related Myopathies}},
  url          = {{http://dx.doi.org/10.3233/JND-200577}},
  doi          = {{10.3233/JND-200577}},
  volume       = {{8}},
  year         = {{2021}},
}