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

Article type: Research Article

Authors: Villar-Quiles, Rocío N.^{a; b} | Donkervoort, Sandra^c | de Becdelièvre, Alix^{d; e} | Gartioux, Corine^b | Jobic, Valérie^e | Foley, A. Reghan^c | McCarty, Riley M.^c | Hu, Ying^c | Menassa, Rita^f | Michel, Laurence^f | Gousse, Gaelle^g | Lacour, Arnaud^h | Petiot, Philippeⁱ | Streichenberger, Nathalie^j | Choumert, Ariane^k | Declerck, Léa^k | Urtizberea, J.A.^l | Sole, Guilhem^m | Furby, Alainⁿ | Cérino, Matthieu^{o; s} | Krahn, Martin^o | Campana- Salort, Emmanuelle^p | Ferreiro, Ana^{a; q} | Eymard, Bruno^a | Bönnemann, Carsten G.^c | Bharucha-Goebel, Diana^{c; t} | Sumner, Charlotte J.^{u; v} | Connolly, Anne M.^w | Richard, Pascale^e | Allamand, Valérie^{b; r} | Métay, Corinne^{e; b; 1} | Stojkovic, Tanya^{a; b; 1; *}

Affiliations: [a] AP-HP, Reference Center for Neuromuscular Disorders, Pitié-Salpêtrière Hospital, Paris, France | [b] Centre de Recherche en Myologie, Institut de Myologie, Sorbonne Université, Inserm, Paris, France | [c] Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA | [d] AP-HP, Département de Génétique, Hôpital Henri Mondor, Créteil, France | [e] AP-HP, Centre de Génétique Moléculaire et Chromosomique, UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire, GH Pitié-Salpêtrière, Paris, France | [f] Hospices Civils de Lyon, LBMMS, Service Biochimie Biologie Moléculaire Grand Est, Groupement Hospitalier Est, CBPE, Bron, France | [g] Service de Neuropédiatrie, CHU Saint-Étienne, Saint-Étienne, France | [h] Service de Neurologie, CHU Saint-Étienne, Saint-Étienne, France | [i] Neurologie et Explorations Fonctionnelles Neurologiques, Centre de Référence Maladies Neuromusculaires de la Région Rhône-Alpes Hôpital de la Croix-Rousse, Lyon, France | [j] Centre de Pathologie et Neuropathologie Est, Hospices Civils de Lyon, Groupement Hospitalier Est, Bron, France | [k] Centre des Maladies Rares Neurologiques, CHU Sud Réunion, Saint-Pierre, France | [l] Hôpital Marin, Centre de Compétence Neuromusculaire, Hendaye, France | [m] Centre de Référence des Maladies Neuromusculaires AOC, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France | [n] Centre de Référence des Maladies Neuromusculaires Rares Rhônes-Alpes, Hôpital Nord, CHU de Saint-Étienne, Saint-Étienne, France | [o] AP-HM, Département de Génétique Médicale, Hôpital Timone Enfants, Assistance Publique Hôpitaux de Marseille, Marseille, France | [p] AP-HM, Centre de Référence des Maladies Neuromusculaires, Hôpital Timone, Marseille, France | [q] Basic and Translational Myology Lab, UMR8251, University Paris Diderot/CNRS, Paris, France | [r] Unit of Muscle Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden | [s] AP-HM, Laboratoire de Biochimie, Hôpital de la Conception, Marseille, France | [t] Division of Neurology, Children’s National Hospital, Washington, DC, USA | [u] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [v] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [w] Department of Pediatrics, Neurology Division, Nationwide Children’s Hospital, Ohio State University, Columbus, OH, USA

Correspondence: [*] Correspondence to: Dr Tanya Stojkovic, Centre de Référence des Maladies Neuromusculaires Nord / Est / Ile-de-France, Groupe Hospitalier Pitié-Salpêtrière, 47–83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: [email protected].

Note: [1] Last co-authors.

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 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.

Keywords: Collagen VI-related myopathies, COL6A3, collagen type VI, neuromuscular disorders, limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD), muscular MRI, NGS

DOI: 10.3233/JND-200577

Journal: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 633-645, 2021