scholarly journals Recent Progress in Oculopharyngeal Muscular Dystrophy

2021 ◽  
Vol 10 (7) ◽  
pp. 1375
Author(s):  
Satoshi Yamashita
Keyword(s):  
Muscular Dystrophy ◽  
Recent Progress ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Limb Weakness ◽  
Medical Needs ◽  
Therapeutic Benefits ◽  
Initial Symptoms ◽  
Swallowing Problems

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset intractable myopathy, characterized by slowly progressive ptosis, dysphagia, and proximal limb weakness. It is caused by the abnormal expansion of the alanine-encoding (GCN)n trinucleotide repeat in the exon 1 of the polyadenosine (poly[A]) binding protein nuclear 1 gene (11–18 repeats in OPMD instead of the normal 10 repeats). As the disease progresses, the patients gradually develop a feeling of suffocation, regurgitation of food, and aspiration pneumonia, although the initial symptoms and the progression patterns vary among the patients. Autologous myoblast transplantation may provide therapeutic benefits by reducing swallowing problems in these patients. Therefore, it is important to assemble information on such patients for the introduction of effective treatments in nonendemic areas. Herein, we present a concise review of recent progress in clinical and pathological studies of OPMD and introduce an idea for setting up a nation-wide OPMD disease registry in Japan. Since it is important to understand patients’ unmet medical needs, realize therapeutically targetable symptoms, and identify indices of therapeutic efficacy, our attempt to establish a unique patient registry of OPMD will be a helpful tool to address these urgent issues.

scholarly journals A Japanese case of oculopharyngeal muscular dystrophy (OPMD) with PABPN1 c.35G > C; p.Gly12Ala point mutation

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yo-suke Nishii ◽  
Yu-ichi Noto ◽  
Rei Yasuda ◽  
Takamasa Kitaoji ◽  
Shinji Ashida ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Point Mutation ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Lower Limbs ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Muscle Involvement ◽  
Case Presentation ◽  
Japanese Case ◽  
Expansion Mutation

Abstract Background Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy characterised by slowly progressive ptosis, dysphagia, and proximal limb muscle weakness. A common cause of OPMD is the short expansion of a GCG or GCA trinucleotide repeat in PABPN1 gene. Case presentation A 78-year-old woman presented with ptosis and gradually progressive dysphagia. Her son had the same symptoms. A physical examination and muscle imaging (MRI and ultrasound) showed impairment of the tongue, proximal muscles of the upper limbs, and flexor muscles of the lower limbs. Needle-electromyography (EMG) of bulbar and facial muscles revealed a myopathic pattern. Based on the characteristic muscle involvement pattern and needle-EMG findings, we suspected that the patient had OPMD. Gene analysis revealed PABPN1 c.35G > C point mutation, which mimicked the effect of a common causative repeat expansion mutation of OPMD. Conclusion We herein describe the first reported Japanese case of OPMD with PABPN1 point mutation, suggesting that this mutation is causative in Asians as well as in Europeans, in whom it was originally reported.

scholarly journals A polyalanine antibody for the diagnosis of oculopharyngeal muscular dystrophy and polyalanine-related diseases

2017 ◽  
Vol 1 ◽  
pp. 1
Author(s):  
Shawn J. Stochmanski ◽  
François Blondeau ◽  
Martine Girard ◽  
Pascale Hince ◽  
Daniel Rochefort ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Causative Mutation ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Spinocerebellar Ataxia Type 3 ◽  
Repeat Tract ◽  
Repeat Expansions

Eighteen severe human diseases have so far been associated with trinucleotide repeat expansions coding for either polyalanine (encoded by a GCN repeat tract) or polyglutamine (encoded by a CAG repeat tract).  Among them, oculopharyngeal muscular dystrophy (OPMD), spinocerebellar ataxia type-3 (SCA3), and Huntington’s disease (HD) are late-onset autosomal-dominant disorders characterized by the presence of intranuclear inclusions (INIs).  We have previously identified the OPMD causative mutation as a small expansion (from 2 in normal to 7 in disease) of a GCG repeat tract in the PABPN1 gene.  In addition, -1 ribosomal frameshifting has been reported to occur in expanded CAG repeat tracts in the ATXN3 (SCA3) and HTT (HD) genes, resulting in the translation of a hybrid CAG/GCA repeat tract and the production of a polyalanine-containing peptide.  Previous studies on OPMD suggest that polyalanine-induced toxicity is very sensitive to the dosage and length of the alanine stretch.  Here we report the characterization of a polyclonal antibody that selectively recognizes pathological expansions of polyalanine in PABPN1.  Furthermore, our antibody also detects the presence of alanine proteins in INIs of SCA3 and HD patient samples.

scholarly journals Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010015
Author(s):  
Cécile Ribot ◽  
Cédric Soler ◽  
Aymeric Chartier ◽  
Sandy Al Hayek ◽  
Rima Naït-Saïdi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Atrophy ◽  
Late Onset ◽  
Oral Treatment ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Functional Study ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Ubiquitin Proteasome ◽  
And Function

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

scholarly journals hnRNP A1 and A/B Interaction with PABPN1 in Oculopharyngeal Muscular Dystrophy

2003 ◽  
Vol 30 (3) ◽  
pp. 244-251 ◽  
Author(s):  
Xueping Fan ◽  
Christiane Messaed ◽  
Patrick Dion ◽  
Janet Laganiere ◽  
Bernard Brais ◽  
...  
Keyword(s):  
Cell Death ◽  
Muscular Dystrophy ◽  
Binding Proteins ◽  
Fetal Brain ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Hnrnp A1 ◽  
Intranuclear Inclusions ◽  
Limb Weakness ◽  
Dominant Form ◽  
Hnrnp Proteins

Background:Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive ptosis, dysphagia and proximal limb weakness. The autosomal dominant form of this disease is caused by short expansions of a (GCG)6 repeat to (GCG)8-13 in the PABPN1 gene. The mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminus of PABPN1. The mutated PABPN1 (mPABPN1) induces the formation of intranuclear filamentous inclusions that sequester poly(A) RNA and are associated with cell death.Methods:Human fetal brain cDNA library was used to look for PABPN1 binding proteins using yeast two-hybrid screen. The protein interaction was confirmed by GST pull-down and co-immunoprecipitation assays. Oculopharyngeal muscular dystrophy cellular model and OPMD patient muscle tissue were used to check whether the PABPN1 binding proteins were involved in the formation of OPMD intranuclear inclusions.Results:We identify two PABPN1 interacting proteins, hnRNP A1 and hnRNP A/B. When co-expressed with mPABPN1 in COS-7 cells, predominantly nuclear protein hnRNP A1 and A/B co-localize with mPABPN1 in the insoluble intranuclear aggregates. Patient studies showed that hnRNP A1 is sequestered in OPMD nuclear inclusions.Conclusions:The hnRNP proteins are involved in mRNA processing and mRNA nucleocytoplasmic export, sequestering of hnRNPs in OPMD intranuclear aggregates supports the view that OPMD intranuclear inclusions are “poly(A) RNA traps”, which would interfere with RNA export, and cause muscle cell death.

scholarly journals Progress in Understanding the Pathogenesis of Oculopharyngeal Muscular Dystrophy

2003 ◽  
Vol 30 (1) ◽  
pp. 8-14 ◽  
Author(s):  
Xueping Fan ◽  
Guy A. Rouleau
Keyword(s):  
Muscular Dystrophy ◽  
Autosomal Dominant ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Intranuclear Inclusions ◽  
Intranuclear Inclusion ◽  
Limb Weakness ◽  
Dominant Form ◽  
Autosomal Dominant Form ◽  
Swallowing Difficulties

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping (ptosis), swallowing difficulties (dysphagia), and proximal limb weakness. The autosomal dominant form of this disease is caused by expansions of a (GCG)6 repeat to (GCG)8-13 in the PABPN1 gene. These mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminal domain of PABPN1. Mutated PABPN1 (mPABPN1) induces the formation of muscle intranuclear inclusions that are thought to be the hallmark of this disease. In this review, we discuss: 1) OPMD genetics and PABPN1 function studies; 2) diseases caused by polyalanine expansions and cellular polyalanine toxicity; 3) mPABPN1-induced intranuclear inclusion toxicity; 4) role of oligomerization of mPABPN1 in the formation and toxicity of OPMD intranuclear inclusions and; 5) recruitment of subcellular components to the OPMD inclusions. We present a potential molecular mechanism for OPMD pathogenesis that accounts for these observations.

scholarly journals Correlation between PABPN1 genotype and disease severity in oculopharyngeal muscular dystrophy

Neurology ◽  
2016 ◽  
Vol 88 (4) ◽  
pp. 359-365 ◽  
Author(s):  
Pascale Richard ◽  
Capucine Trollet ◽  
Tanya Stojkovic ◽  
Alix de Becdelievre ◽  
Sophie Perie ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Disease Severity ◽  
Severe Disease ◽  
Statistical Correlation ◽  
Age At Diagnosis ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Gene Encoding ◽  
Limb Weakness ◽  
Polyalanine Expansion ◽  
The Mean

Objective:Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant adult-onset disease characterized by progressive ptosis, dysphagia, and proximal limb weakness. The genetic cause is an expanded (GCN)n mutation in the PABPN1 gene encoding for the polyadenylate-binding protein nuclear 1. We hypothesized a potential correlation between the size of the (GCN)n expansion and the severity of the phenotype. To do this, we characterized the distribution of the genotypes as well as their correlation with age at diagnosis and phenotypical features in a large cohort of heterozygous and homozygous patients with OPMD in France with a confirmed molecular diagnosis of PABPN1.Methods:We explored 354 unrelated index cases recruited between 1999 and 2014 in several neuromuscular centers in France.Results:This cohort allowed us to characterize the frequency of mutated alleles in the French population and to demonstrate a statistical correlation between the size of the expansion and the mean age at diagnosis. We also confirmed that homozygous patients present with a more severe disease.Conclusions:It has been difficult to establish phenotype–genotype correlations because of the rare nature of this disease. Our work demonstrates that patients with OPMD with longer PABPN1 expansion are on average diagnosed at an earlier age than patients with a shorter expansion, confirming that polyalanine expansion size plays a role in OPMD, with an effect on disease severity and progression.

Late onset oculopharyngeal muscular dystrophy with prominent neurogenic features and short GCG trinucleotide expansion

2010 ◽  
Vol 43 (1) ◽  
pp. 141-142 ◽  
Author(s):  
Giovanni Piccolo ◽  
Andrea Cortese ◽  
Eleonora Tavazzi ◽  
Laura Piccolo ◽  
Jenny Sassone ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Late Onset ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Trinucleotide Expansion

scholarly journals Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype

2018 ◽  
Author(s):  
Alberto Malerba ◽  
Fanny Roth ◽  
Pradeep Harish ◽  
Jamila Dhiab ◽  
Ngoc Lu-Nguyen ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Genetic Disease ◽  
Late Onset ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Systemic Delivery ◽  
Active Constituent ◽  
Eukaryotic Translation ◽  
Pharyngeal Muscles ◽  
The Unfolded Protein Response

AbstractOculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease affecting most profoundly eyelid and pharyngeal muscles, leading respectively to ptosis and dysphagia, and proximal limb muscles at later stages. A short abnormal (GCG) triplet expansion in the polyA– binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. It is commonly accepted that aggregates themselves, the aggregation process and/or the early oligomeric species of PABPN1 are toxic in OPMD. Decreasing PABPN1 aggregate load in animal models of OPMD ameliorates the muscle phenotype. In order to identify a potential therapeutic molecule that would prevent and reduce aggregates, we tested guanabenz acetate (GA), an FDA-approved antihypertensive drug, in OPMD cells as well as in the A17 OPMD mouse model. We demonstrate that treating mice with GA reduces the size and number of nuclear aggregates, improves muscle force, protects myofibres from the pathology-derived turnover and decreases fibrosis. GA is known to target various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. Here we used a cellular model of OPMD to demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiator factor 2α subunit (eIF2α) and the splicing of Xbp1, key components of the UPR. Altogether these data suggest that modulation of protein folding regulation can be beneficial for OPMD and support the further development of guanabenz or its derivatives for treatment of OPMD in humans.Significance StatementOculopharyngeal muscular dystrophy (OPMD) is a rare late onset incurable genetic disease characterized by the formation of insoluble aggregates in skeletal muscles. It has been shown that the reduction of aggregates correlates with an improvement of the disease. Here we used a mouse model of OPMD to show that Guanabenz acetate, the active constituent of a marketed but recently discontinued drug for hypertension, decreases the number and the size of aggregates after systemic delivery and improves many aspects of the disease. We also describe experimental evidences explaining the mechanism behind the efficacy of such compound for OPMD.

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