Aquaporin-4 expression is severely reduced in human sarcoglycanopathies and dysferlinopathies

Assereto, Stefania; Mastrototaro, M.; Stringara, Silvia; Gazzerro, Elisabetta; Broda, Paolo; Nicchia, Grazia Paola; Svelto, María; Bruno, Claudio; Nigro, Vincenzo; Lisanti, Michael P.; Frigeri, Antonio; Minetti, Carlo

doi:10.4161/cc.7.14.6272

Cited by 19 publications

(21 citation statements)

References 38 publications

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“…Lama2 encodes a protein known to interact directly with the dystrophin complex, and mutations in Lama2 lead to muscular dystrophy (8,29). Aqp4 encodes aquaporin 4, a protein noted to be reduced in multiple forms of muscular dystrophy (1,6). Also in this region is Mib1, the mammalian ortholog of Drosophila Mib2, a gene linked to muscle growth (3).…”

Section: Discussionmentioning

confidence: 99%

Distinct genetic regions modify specific muscle groups in muscular dystrophy

Swaggart¹,

Heydemann

Palmer³

et al. 2011

Physiological Genomics

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Phenotypic expression in the muscular dystrophies is variable, even with the identical mutation, providing strong evidence that genetic modifiers influence outcome. To identify genetic modifier loci, we used quantitative trait locus mapping in two differentially affected mouse strains with muscular dystrophy. Using the Sgcg model of limb girdle muscular dystrophy that lacks the dystrophin-associated protein γ-sarcoglycan, we evaluated chromosomal regions that segregated with two distinct quantifiable characteristics of muscular dystrophy, membrane permeability and fibrosis. We previously identified a single major locus on murine chromosome 7 that influences both traits of membrane permeability and fibrosis in the quadriceps muscle. Using a larger cohort, we now found that this same interval strongly associated with both traits in all limb skeletal muscle groups studied, including the gastrocnemius/soleus, gluteus/hamstring, and triceps muscles. In contrast, the muscles of the trunk were modified by distinct genetic loci, possibly reflecting the embryological origins and physiological stressors unique to these muscle groups. A locus on chromosome 18 was identified that modified membrane permeability of the abdominal muscles, and a locus on chromosome 3 was found that regulated diaphragm and abdominal muscle fibrosis. Fibrosis in the heart associated with a region on chromosome 9 and likely reflects differential function between cardiac and skeletal muscle. These data underscore the complexity of inheritance and penetrance of single-gene disorders.

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Section: Discussionmentioning

confidence: 99%

Distinct genetic regions modify specific muscle groups in muscular dystrophy

Swaggart¹,

Heydemann

Palmer³

et al. 2011

Physiological Genomics

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show abstract

“…Recently, aquaporin 4, a muscle-specific water channel, was shown to be associated with sarcoglycan through α1-syntrophin, an interaction validated by its severe reduction in muscles of sarcoglycanopathy patients (Ref. 32). …”

Section: Role Of Sarcoglycans In the Dystrophin–glycoprotein Complexmentioning

confidence: 99%

Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects

Sandonà

Betto

2009

Expert Rev. Mol. Med.

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Sarcoglycanopathies are a group of autosomal recessive muscle-wasting disorders caused by genetic defects in one of four cell membrane glycoproteins, α-, β-, γ- or δ-sarcoglycan. These four sarcoglycans form a subcomplex that is closely linked to the major dystrophin-associated protein complex, which is essential for membrane integrity during muscle contraction and provides a scaffold for important signalling molecules. Proper assembly, trafficking and targeting of the sarcoglycan complex is of vital importance, and mutations that severely perturb tetramer formation and localisation result in sarcoglycanopathy. Gene defects in one sarcoglycan cause the absence or reduced concentration of the other subunits. Most genetic defects generate mutated proteins that are degraded through the cell's quality control system; however, in many cases, conformational modifications do not affect the function of the protein, yet it is recognised as misfolded and prematurely degraded. Recent evidence shows that misfolded sarcoglycans could be rescued to the cell membrane by assisting their maturation along the ER secretory pathway. This review summarises the etiopathogenesis of sarcoglycanopathies and highlights the quality control machinery as a potential pharmacological target for therapy of these genetic disorders.

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“…AQP4 is expressed in healthy brain and muscle tissues (39) and well known to associate with neuromyelitis optica. The AQP4 expression is also reduced in the skeletal muscle in patients with Duchenne muscular dystrophy, Fukuyama-type congenital muscular dystrophy, and sarcoglycanopathy (39)(40)(41). In the present study, the IHC analysis revealed a decrease in the AQP4 expression in both regenerating fibers and many non-necrotic fibers in patients with IMs, particularly PM.…”

Section: Discussionmentioning

confidence: 58%

Gene Expression Profile of Inflammatory Myopathy with Malignancy is Similar to that of Dermatomyositis rather than Polymyositis

et al. 2016

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Objective An association has been reported between inflammatory myopathies (IMs), which include polymyositis (PM) and dermatomyositis (DM), and malignancy, and the concept of cancer-associated myositis (CAM) was recently proposed. We herein attempted to determine the features and etiologies of these myopathies. Methods We analyzed the gene expression levels via microarray and real-time quantitative reverse transcription polymerase chain reaction analyses to identify genes that were specifically upregulated or downregulated with suspected inflammatory involvement and verified the microarray data via an immunohistochemical (IHC) analysis in additional cases. Patients We selected 14 patients with the following conditions: PM without malignancy (n=3), DM without malignancy (n=3), CAM (n=3), and Controls (no pathological changes or malignancy; n=5). Results PM was distinct from DM and CAM in a clustering analysis and exhibited the highest numbers of overexpressed genes and specific pathologies in a gene ontology analysis. The IHC analysis confirmed the gene expression results. Conclusion PM is associated with severe inflammatory pathological findings, primarily in the cell-mediated immune system. DM and CAM exhibit similarities in the gene expression and IHC results, which suggest that humoral immunity is the main etiology for both myopathies, indicating the importance of cancer screening in patients with IMs, particularly DM.

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Aquaporin-4 expression is severely reduced in human sarcoglycanopathies and dysferlinopathies

Cited by 19 publications

References 38 publications

Distinct genetic regions modify specific muscle groups in muscular dystrophy

Distinct genetic regions modify specific muscle groups in muscular dystrophy

Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects

Gene Expression Profile of Inflammatory Myopathy with Malignancy is Similar to that of Dermatomyositis rather than Polymyositis

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