Homozygosity of the Dominant Myotilin c.179C>T (p.Ser60Phe) Mutation Causes a More Severe and Proximal Muscular Dystrophy

Article type: Research Article

Authors: Rudolf, Gabrielle^{a; b; *} | Suominen, Tiina^c | Penttilä, Sini^c | Hackman, Peter^d | Evilä, Anni^d | Lannes, Béatrice^e | Echaniz-Laguna, Andoni^b | Bierry, Guillaume^f | Tranchant, Christine^{a; b; g; 1} | Udd, Bjarne^{d; e; h; 1; *}

Affiliations: [a] IGBMC, CNRS UMR 7104, INSERM U964, Strasbourg University, France | [b] Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France | [c] Neuromuscular Research Unit, University of Tampere and Tampere University Hospital, Tampere, Finland | [d] Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland | [e] Département d’Anatomopathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France | [f] Département de Radiologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France | [g] Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, Universitdé Strasbourg, INSERM, Illkirch, France | [h] Department of Neurology, Vaasa Central Hospital, Vaasa, Finland

Correspondence: [*] Correspondence to: Gabrielle Rudolf, IGBMC, CNRS UMR 7104, INSERM U964, Strasbourg University, France. Tel.: +33 333 8812 8639; Fax: +33 333 8812 8533; E-mail: Gabrielle.Rudolf@chru-strasbourg.fr and Bjarne Udd, Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland. Tel.: +35 891 912 5075; Fax: +35 891 912 5073; E-mail: Bjarne.udd@nettika.fi.

Note: [1] These authors contributed equally to this work and should be considered as co-last authors.

Abstract: Most myotilinopathy patients present with a dominant late onset distal phenotype and myofibrillar pathology, although the first MYOT mutation in a family reported to have LGMD phenotype. We report here a French family affected with a late onset proximal and distal muscle weakness and myofibrillar myopathy on muscle pathology, in which the siblings known to be clinically affected were homozygous for the c.179C>T (p.Ser60Phe) myotilin gene mutation. One subjectively asymptomatic member of the family was heterozygous for this mutation. This is the first report of a family with patients being homozygous for a known dominant MYOT mutation. Dominant negative mutations are generally considered not to cause a more severe disease in homozygosity, but our data clearly demonstrate the existence of dominant MYOT mutations with a possible dose effect causing a more severe disease phenotype in homozygosity in the spectrum of myofibrillar myopathies (MFM).

Keywords: Molecular genetics, myotilin homozygosity, myofibrillar myopathy, MYOT, c.179C>T (p.Ser60Phe)

DOI: 10.3233/JND-150143

Journal: Journal of Neuromuscular Diseases, vol. 3, no. 2, pp. 275-281, 2016