A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: distinct histopathological outcomes compared with desminopathies

Çetin, Nilgün; Balcı-Hayta, Burcu; Gündeşli, Hülya; Korkusuz, Petek; Puralı, Nuhan; Talim, Beril; Tan, Ersin; Selcen, Duygu; Özdamar, Sevim Erdem; Dinçer, Pervin

doi:10.1136/jmedgenet-2012-101487

Cited by 64 publications

(48 citation statements)

References 26 publications

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“…3A-E) [21,22]. This pattern is distinguishable from myopathic features which exhibit degenerative ultrastructural changes starting from the myocytic plasma membrane [23].…”

Section: Discussionmentioning

confidence: 94%

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Kayman-Kurekci

Talim

Korkusuz

et al. 2014

Neuromuscular Disorders

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We performed genome-wide homozygosity mapping and mapped a novel myopathic phenotype to chromosomal region 1q25 in a consanguineous family with three affected individuals manifesting proximal and distal weakness and atrophy, rigid spine and contractures of the proximal and distal interphalangeal hand joints. Additionally, cardiomyopathy and respiratory involvement were noted. DNA sequencing of torsinA-interacting protein 1 (TOR1AIP1) gene encoding lamina-associated polypeptide 1B (LAP1B), showed a homozygous c.186delG mutation that causes a frameshift resulting in a premature stop codon (p.E62fsTer25). We observed that expression of LAP1B was absent in the patient skeletal muscle fibres. Ultrastructural examination showed intact sarcomeric organization but alterations of the nuclear envelope including nuclear fragmentation, chromatin bleb formation and naked chromatin. LAP1B is a type-2 integral membrane protein localized in the inner nuclear membrane that binds to both A-and B-type lamins, and is involved in the regulation of torsinA ATPase. Interestingly, luminal domain-like LAP1 (LULL1)-an endoplasmic reticulum-localized partner of torsinA-was overexpressed in the patient's muscle in the absence of LAP1B. Therefore, the findings suggest that LAP1 and LULL1 might have a compensatory effect on each other. This study expands the spectrum of genes associated with nuclear envelopathies and highlights the critical function for LAP1B in striated muscle.

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“…3A-E) [21,22]. This pattern is distinguishable from myopathic features which exhibit degenerative ultrastructural changes starting from the myocytic plasma membrane [23].…”

Section: Discussionmentioning

confidence: 94%

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Kayman-Kurekci

Talim

Korkusuz

et al. 2014

Neuromuscular Disorders

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“…The proteins in cluster K5 that were identified in both this and the original analysis are depicted in blue, whereas the proteins depicted in gray represent “missing links.” Known DGC components are shown with red borders, and proteins that bind directly to them with green borders. Inspection of this PPI map revealed proteins that are mutated in muscular dystrophies and had not previously been linked to the classical DGC (42, 43). For example, plectin1 (PLEC1) is linked to several DGC components, and also to MYZAP, mutant forms of which are associated with severe skeletal-muscle dysfunction (44).…”

Section: Resultsmentioning

confidence: 99%

Molecular Signatures of Membrane Protein Complexes Underlying Muscular Dystrophy

Turk

Hsiao

Smits

et al. 2016

Molecular & Cellular Proteomics

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Mutations in genes encoding components of the sarcolemmal dystrophin-glycoprotein complex (DGC) are responsible for a large number of muscular dystrophies. As such, molecular dissection of the DGC is expected to both reveal pathological mechanisms, and provides a biological framework for validating new DGC components. Establishment of the molecular composition of plasma-membrane protein complexes has been hampered by a lack of suitable biochemical approaches. Here we present an analytical workflow based upon the principles of protein correlation profiling that has enabled us to model the molecular composition of the DGC in mouse skeletal muscle. We also report our analysis of protein complexes in mice harboring mutations in DGC components. Bioinformatic analyses suggested that cell-adhesion pathways were under the transcriptional control of NFκB in DGC mutant mice, which is a finding that is supported by previous studies that showed NFκB-regulated pathways underlie the pathophysiology of DGC-related muscular dystrophies. Moreover, the bioinformatic analyses suggested that inflammatory and compensatory mechanisms were activated in skeletal muscle of DGC mutant mice. Additionally, this proteomic study provides a molecular framework to refine our understanding of the DGC, identification of protein biomarkers of neuromuscular disease, and pharmacological interrogation of the DGC in adult skeletal muscle https://www.mda.org/disease/congenital-muscular-dystrophy/research.

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“…Finally, a mutation in the desmin gene, which encodes for desmin—an intermediate filament, is related to LGMD2R without cardiomyopathy. LGMD2R patients have progressive proximal muscle weakness and nonspecific atrophy affecting both the lower and upper limbs (Cetin et al, ).…”

Section: Sarcomere Complexmentioning

confidence: 99%

Prevalence, pathological mechanisms, and genetic basis of limb‐girdle muscular dystrophies: A review

Taghizadeh

Rezaee

Barreto

et al. 2018

Journal Cellular Physiology

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Limb‐girdle muscular dystrophies (LGMDs) are a highly heterogeneous group of neuromuscular disorders that are associated with weakness and wasting of muscles in legs and arms. Signs and symptoms may begin at any age and usually worsen by time. LGMDs are autosomal disorders with different types and their prevalence is not the same in different areas. New technologies such as next‐generation sequencing can accelerate their diagnosis. Several important pathological mechanisms that are involved in the pathology of the LGMD include abnormalities in dystrophin–glycoprotein complex, the sarcomere, glycosylation of dystroglycan, vesicle and molecular trafficking, signal transduction pathways, and nuclear functions. Here, we provide a comprehensive review that integrates LGMD clinical manifestations, prevalence, and some pathological mechanisms involved in LGMDs.

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A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: distinct histopathological outcomes compared with desminopathies

Abstract: Our study reveals that autosomal recessive mutations in DES cause LGMD2 phenotype without features of myofibrillar myopathy.

Cited by 64 publications

References 26 publications

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Molecular Signatures of Membrane Protein Complexes Underlying Muscular Dystrophy

Prevalence, pathological mechanisms, and genetic basis of limb‐girdle muscular dystrophies: A review

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