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.
Highlights
Four-and-half LIM domain protein 1 (FHL1) is a cysteine-rich double zinc-finger protein encoded by the FHL1 gene, localized on chromosome X (Dawid et al, 1995; Kadrmas and Beckerle, 2004)
The most striking contractures were in the neck muscles causing a fixed hyperextended neck that was impossible to move in any direction
In this work, we provided data showing that aggresome and autophagy are involved in the pathophysiological defects underlying the muscle pathology of a sarcopenic patient with rigid spine syndrome (RSS) and carrying a FHL1 p.C150R mutation
Summary
Four-and-half LIM domain protein 1 (FHL1) is a cysteine-rich double zinc-finger protein encoded by the FHL1 gene, localized on chromosome X (Dawid et al, 1995; Kadrmas and Beckerle, 2004). Four-and-half LIM domain protein 1 is highly expressed in skeletal and cardiac muscles (Lee et al, 1998; Brown et al, 1999; Greene et al, 1999; Morgan and Madgwick, 1999), where it localizes in the myofibrillar sarcomeres and in the sarcolemma (Bertrand et al, 2014) This protein has been demonstrated to be involved in several processes, including cellular architecture (McGrath et al, 2003, 2006), myoblast differentiation (Lee et al, 2012), mechanotransduction (Sheikh et al, 2008), and myofiber size (Cowling et al, 2008). FHL1 binds signaling and cytoskeletal proteins as well as transcription factors, acting as a transcriptional regulator of nuclear factor of activated T cells (NFATc1) to enhance the expression of genes that increase myofiber size (Cowling et al, 2008)
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