title: Aggresome-Autophagy Involvement in a Sarcopenic Patient with Rigid Spine Syndrome and a p.C150R Mutation in FHL1 Gene.
abstract: The four-and-half LIM domain protein 1 (FHL1) is highly expressed in skeletal and cardiac muscle. Mutations of the FHL1 gene have been associated with diverse chronic myopathies including reducing body myopathy, rigid spine syndrome (RSS), and Emery-Dreifuss muscular dystrophy. We investigated a family with a mutation (p.C150R) in the second LIM domain of FHL1. In this family, a brother and a sister were affected by RSS, and their mother had mild lower limbs weakness. The 34-year-old female had an early and progressive rigidity of the cervical spine and severe respiratory insufficiency. Muscle mass evaluated by DXA was markedly reduced, while fat mass was increased to 40%. CT scan showed an almost complete substitution of muscle by fibro-adipose tissue. Muscle biopsy showed accumulation of FHL1 throughout the cytoplasm and around myonuclei into multiprotein aggregates with aggresome/autophagy features as indicated by ubiquitin, p62, and LC3 labeling. DNA deposits, not associated with nuclear lamina components and histones, were also detected in the aggregates, suggesting nuclear degradation. Ultrastructural analysis showed the presence of dysmorphic nuclei, accumulation of tubulofilamentous and granular material, and perinuclear accumulation of autophagic vacuoles. These data point to involvement of the aggresome-autophagy pathway in the pathophysiological mechanism underlying the muscle pathology of FHL1 C150R mutation.
authors.affiliation: Institute of Molecular Genetics, CNR-National Research Council of Italy , Bologna , Italy ; SC Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute , Bologna , Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
authors.affiliation: Department of Molecular Medicine, University of Padova , Padova , Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Castagnaro
authors.affiliation: Institute of Molecular Genetics, CNR-National Research Council of Italy , Bologna , Italy ; SC Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute , Bologna , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: Department of Molecular Medicine, University of Padova , Padova , Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Chrisam
authors.affiliation: Institute of Molecular Genetics, CNR-National Research Council of Italy , Bologna , Italy ; SC Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute , Bologna , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sardone
authors.affiliation: UF Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Groupe Hospitalier Pitié-Salpêtrière , Paris , France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Demay
authors.affiliation: UF Cardiogénétique et Myogénétique, Centre de Génétique, Hôpitaux Universitaires de la Pitié Salpêtrière , Paris , France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.affiliation: Institute of Molecular Genetics, CNR-National Research Council of Italy , Bologna , Italy ; SC Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute , Bologna , Italy.
authors.forename: Spartaco
authors.initials: S
authors.lastname: Santi
authors.affiliation: Institute of Molecular Genetics, CNR-National Research Council of Italy , Bologna , Italy.
authors.forename: Nadir M
authors.initials: NM
authors.lastname: Maraldi
authors.affiliation: SC Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute , Bologna , Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.affiliation: Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine , Padova , Italy ; Department of Biomedical Science, University of Padova , Padova , Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: Department of Molecular Medicine, University of Padova , Padova , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
keywords: FHL1; autophagy; myopathy; protein aggregates; sarcopenia