A dysfunctional desmin mutation in a patient with severe generalized myopathy

A dysfunctional desmin mutation in a patient with severe generalized myopathy

^*Fundación Echevarne, 08037 Barcelona, Spain; Departments of ^†Pathology and ^‖Neurology, Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona, 08916 Badalona, Barcelona, Spain; ^¶Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205; and ^§Howard Hughes Medical Institute and Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637

Contributed by Elaine Fuchs

Abstract

Mice lacking desmin produce muscle fibers with Z disks and normal sarcomeric organization. However, the muscles are mechanically fragile and degenerate upon repeated contractions. We report here a human patient with severe generalized myopathy and aberrant intrasarcoplasmic accumulation of desmin intermediate filaments. Muscle tissue from this patient lacks the wild-type desmin allele and has a desmin gene mutation encoding a 7-aa deletion within the coiled-coil segment of the protein. We show that recombinant desmin harboring this deletion cannot form proper desmin intermediate filament networks in cultured cells, nor is it able to assemble into 10-nm filaments in vitro. These findings provide direct evidence that a mutation in desmin can cause human myopathies.

Footnotes

↵ ‡ A.M.M.-M. and G.S. contributed equally to this work.
↵ ** To whom reprint requests should be addressed at: Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, The University of Chicago, 5841 S. Maryland Avenue, Room N314, Chicago, IL 60637. e-mail: lain{at}midway.uchicago.edu.
ABBREVIATIONS:

IF,

intermediate filament;

CMV,

cytomegalovirus;

SSCP,

single-stranded conformation polymorphism