Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome

INSERM U523, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris CEDEX 13, France.
Nature Genetics (Impact Factor: 29.35). 08/2001; 29(1):17-18. DOI: 10.1038/ng713


One form of congenital muscular dystrophy, rigid spine syndrome (MIM 602771), is a rare neuromuscular disorder characterized by early rigidity of the spine and respiratory insufficiency. A locus on 1p35−36 (RSMD1) was recently found to segregate with rigid spine muscular dystrophy 1 (ref. 1). Here we refine the locus and find evidence of linkage disequilibrium associated with SEPN1, which encodes the recently described selenoprotein N (ref. 2). Our identification and analysis of mutations in SEPN1 is the first description of a selenoprotein implicated in a human disease.

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    • "In our family, the female index case and her brother had a typical RSS (Moghadaszadeh et al., 2001). The p.C150R mutation has already been reported in patients with RSS (Schessl et al., 2010; Selcen et al., 2011). "
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    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.
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    • ". SEPN1-RM and RYR1-RM: The muscle pathology spectrum of SEPN1-RM is broad and includes most but not all cases of Rigid Spine Muscular Dystrophy (RSMD1) [130], classic multi-minicore disease [102], desmin-related myopathy with Mallory body-like inclusions [131] and in a small percentage of congenital fiber type disproportion (CFTD) cases [105]. Most SEPN1-RM muscle biopsies show small focal areas of mitochondria depletion and sarcomere disorganization (minicores) on oxidative stains in muscle fibers, together with type 1 fiber predominance and variable atrophy, protein aggregates and endomysial fibrosis. "
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    ABSTRACT: Congenital muscular dystrophies (CMDs) are early onset disorders of muscle with histological features suggesting a dystrophic process. The congenital muscular dystrophies as a group encompass great clinical as well genetic heterogeneity so that achieving an accurate genetic diagnosis has become increasingly challenging, even in the age of next generation sequencing. In this document we review the diagnostic features, differential diagnostic considerations and available diagnostic tools for the various CMD subtypes and provide a systematic guide to the use of these resources for achieving an accurate molecular diagnosis. An International Committee on the Standard of Care for Congenital Muscular Dystrophies composed of experts on various aspects relevant to the CMDs performed a review of the available literature as well as of the unpublished expertise represented by the members of the committee and their contacts. This process was refined by two rounds of online surveys and followed by a three-day meeting at which the conclusions were presented and further refined. The combined consensus summarized in this document allows the physician to recognize the presence of a CMD in a child with weakness based on history, clinical examination, muscle biopsy results, and imaging. It will be helpful in suspecting a specific CMD subtype in order to prioritize testing to arrive at a final genetic diagnosis.
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    • "The defining histological feature is the presence in a large proportion of muscle fibers of minicores, short regions of sarcomeric disorganization with few or no mitochondria [4]. Mutations in the genes SEPN1 and RYR1 explain many but not all cases of MmD [5–8]. "
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