TY - JOUR
T1 - Clinical and Molecular Spectrum Associated with COL6A3 c.7447A>G p.(Lys2483Glu) Variant
T2 - Elucidating its Role in Collagen VI-related Myopathies
AU - Villar-Quiles, Rocío N.
AU - Donkervoort, Sandra
AU - De Becdelièvre, Alix
AU - Gartioux, Corine
AU - Jobic, Valérie
AU - Foley, A. Reghan
AU - McCarty, Riley M.
AU - Hu, Ying
AU - Menassa, Rita
AU - Michel, Laurence
AU - Gousse, Gaelle
AU - Lacour, Arnaud
AU - Petiot, Philippe
AU - Streichenberger, Nathalie
AU - Choumert, Ariane
AU - Declerck, Leá
AU - Urtizberea, J. A.
AU - Sole, Guilhem
AU - Furby, Alain
AU - Cérino, Matthieu
AU - Krahn, Martin
AU - Campana- Salort, Emmanuelle
AU - Ferreiro, Ana
AU - Eymard, Bruno
AU - Bönnemann, Carsten G.
AU - Bharucha-Goebel, Diana
AU - Sumner, Charlotte J.
AU - Connolly, Anne M.
AU - Richard, Pascale
AU - Allamand, Valérie
AU - Métay, Corinne
AU - Stojkovic, Tanya
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - COL6A3
KW - collagen type VI
KW - Collagen VI-related myopathies
KW - congenital muscular dystrophy (CMD)
KW - limb-girdle muscular dystrophy (LGMD)
KW - muscular MRI
KW - neuromuscular disorders
KW - NGS
U2 - 10.3233/JND-200577
DO - 10.3233/JND-200577
M3 - Article
C2 - 33749658
AN - SCOPUS:85112029214
VL - 8
SP - 633
EP - 645
JO - Journal of Neuromuscular Diseases
JF - Journal of Neuromuscular Diseases
SN - 2214-3599
IS - 4
ER -