title: Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene.
abstract: Desmin-related myopathies (DRMs) are a heterogeneous group of muscle disorders, morphologically defined by intrasarcoplasmic aggregates of desmin. Mutations in the desmin and the alpha-B crystallin genes account for approximately one third of the DRM cases. The genetic basis of the other forms remain unknown, including the early-onset, recessive form with Mallory body-like inclusions (MB-DRMs), first described in five related German patients. Recently, we identified the selenoprotein N gene (SEPN1) as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: rigid spine muscular dystrophy and the severe form of classical multiminicore disease. The finding of Mallory body-like inclusions in two cases of genetically documented SEPN-RM led us to suspect a relationship between MB-DRM and SEPN1. In the original MB-DRM German family, we demonstrated a linkage of the disease to the SEPN1 locus (1p36), and subsequently a homozygous SEPN1 deletion (del 92 nucleotide -19/+73) in the affected patients. A comparative reevaluation showed that MB-DRM and SEPN-RM share identical clinical features. Therefore, we propose that MB-DRM should be categorized as SEPN-RM. These findings substantiate the molecular heterogeneity of DRM, expand the morphological spectrum of SEPN-RM, and implicate a necessary reassessment of the nosological boundaries in early-onset myopathies.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. a.ferreiro@myologie.chups.jussieu.fr
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreiro
authors.forename: Chantal
authors.initials: C
authors.lastname: Ceuterick-de Groote
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Marks
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goemans
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schreiber
authors.forename: Folker
authors.initials: F
authors.lastname: Hanefeld
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Hans H
authors.initials: HH
authors.lastname: Goebel
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
mesh_terms: D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003893:Desmin / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D051140:Selenoproteins
chemical_list: D003893:Desmin; C027596:Mallory body protein, human; D009124:Muscle Proteins; D011506:Proteins; C435489:SELENON protein, human; D051140:Selenoproteins