HUMAN MUTATION 27(9), 906^913, 2006 RESEARCH ARTICLE Variable Pathogenic Potentials of Mutations Located in the Desmin Alpha-Helical Domain Bertrand Goudeau, 1 Fernando Rodrigues-Lima, 2,3 Dirk Fischer, 1 Monique Casteras-Simon, 1,3 Nyamkhishig Sambuughin, 4 Marianne de Visser, 5 Pascal Laforet, 6 Xavier Ferrer, 7 Franc - oise Chapon, 8 Gunnar Sjo ¨berg, 9 Anna Kostareva, 9,10 Thomas Sejersen, 9 Marinos C. Dalakas, 4 Lev G. Goldfarb, 4 and Patrick Vicart 1,3Ã 1 EA300, Universite ´ Paris 7 Denis Diderot, Paris, France; 2 EA1553, Universite ´ Paris 7 Denis Diderot, Paris, France; 3 UFR de Biochimie, Universite ´ Paris 7 Denis Diderot, Paris, France; 4 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; 5 Department of Neurology, University of Amsterdam Medical Centre, Amsterdam, The Netherlands; 6 INSERM U582, Institut de Myologie, Groupe Hospitalier Pitie ´-Salpe ˆtrie `re, Paris, France; 7 Service de Neuropathologie, Universite ´ Victor Segalen, Pessac, Bordeaux, France; 8 Laboratoire de Neuropathologie, Centre Hospitalier Universitaire de Caen, Caen, France; 9 Department of Woman & Child Health and Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; 10 Department of Internal Medicine, Pavlov Medical University, St. Petersburg, Russia Communicated by Haig Kazazian Mutations in the desmin gene have been recognized as a cause of desminopathy, a familial or sporadic disorder characterized by skeletal muscle weakness, often associated with cardiomyopathy or respiratory insufficiency. Distinctive histopathologic features include aberrant intracytoplasmic accumulation of desmin (DES). We present here comparative phenotypic, molecular, and functional characteristics of four novel and three previously reported, but not fully characterized, desmin mutations localized in desmin alpha-helical domain. The results indicate that the c.638C4T (p.A213V), c.1178A4T (p.N393I), and to some extent the c.1078G4C (p.A360P) mutations exhibit pathogenic potentials only if combined with other mutations in desmin or other genes and should therefore be considered conditionally pathogenic. The c.1009G4C (p.A337P), c.1013T4G (p.L338R), c.1195G4T (p.D399Y), and c.1201G4A (p.E401K) mutations make desmin filaments dysfunctional and are capable of causing disease. The pathogenic potentials of desmin mutations correlate with the type and location of the disease-associated mutations in the relatively large and structurally and functionally complex desmin molecule. Mutations within the highly conserved alpha-helical structures are especially damaging since the integrity of the alpha-helix is critical for desmin filament assembly and stability. Hum Mutat 27(9), 906–913, 2006. Published 2006 Wiley-Liss, Inc. y KEY WORDS: myofibrillar myopathy; MFM; distal myopathy; desmin-related myopathy; DRM; desminopathy; cardiomyopathy; desmin gene mutations; DES INTRODUCTION Desminopathy (MIM] 601419) is a distinct group of hereditary myopathies associated with mutations in desmin (DES; MIM] 125660) [Goebel and Warlo, 2000; Goldfarb et al., 2004]. The illness presents with gait disturbance due to progressive muscle weakness in the lower limbs, spreading to involve upper extremities, truncal, neck-flexor, facial, bulbar, and respiratory muscles [Fardeau et al., 1978; Dalakas et al., 2000]. Cardiomyo- pathy is a significant and frequent component of this disease, manifesting with conduction blocks, arrhythmias, and restrictive or dilated cardiac dysfunction, resulting in premature sudden death. Cardiomyopathy may develop long before the onset of skeletal muscle disease, or simultaneously with skeletal myopathy [Dalakas et al., 2000]. Sections of the affected skeletal and cardiac muscles show atrophic fibers with intracytoplasmic accumulation of inclusion bodies and amorphous granulofilamen- tous material; immunostaining for desmin is positive in each region containing abnormal aggregates [Fardeau et al., 1978; Dalakas et al., 2000]. Desmin is a 53-kDa muscle-specific intermediate filament protein of skeletal, cardiac, and smooth muscles that encircles the Z disks to connect and bind them to the plasma membrane and Published online 24 July 2006 in Wiley InterScience (www. interscience.wiley.com). y This article is a US Government work, and as such, is in the public domain in the United States of America. DOI 10.1002/humu.20351 The Supplementary Material referred to in this article can be accessed at http://www.interscience.wiley.com/jpages/1059-7794/ suppmat. Received 15 September 2005; accepted revised manuscript 5 March 2006. Grant sponsor: Association Franc - aise contre les Myopathies (AFM); Grant number: 9878; Grant sponsor: Deutsche Forschungsge- meinschaft; Grant number: Fi 913/2-1. Ã Correspondence to: PatrickVicart, EA300 ‘‘Stress et pathologies du cytosquelette’’, UFR de Biochimie,Tour 42,4e Ø me e Ł tage, case 7006, Universite Ł Paris 7 Denis Diderot,2 placeJussieu,75005 Paris, France. E-mail: patrick.vicart@paris7.jussieu.fr PUBLISHED 2006 WILEY-LISS, INC.