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.

Soluble expanded PABPN1 promotes cell death in oculopharyngeal muscular dystrophy

2007 ◽  
Vol 26 (3) ◽  
pp. 546-557 ◽  
Author(s):  
Christiane Messaed ◽  
Patrick A. Dion ◽  
Aida Abu-Baker ◽  
Daniel Rochefort ◽  
Janet Laganiere ◽  
...  
Keyword(s):  
Cell Death ◽  
Muscular Dystrophy ◽  
Oculopharyngeal Muscular Dystrophy

scholarly journals Lithium chloride attenuates cell death in oculopharyngeal muscular dystrophy by perturbing Wnt/β-catenin pathway

2013 ◽  
Vol 4 (10) ◽  
pp. e821-e821 ◽  
Author(s):  
A Abu-Baker ◽  
J Laganiere ◽  
R Gaudet ◽  
D Rochefort ◽  
B Brais ◽  
...  
Keyword(s):  
Cell Death ◽  
Muscular Dystrophy ◽  
Lithium Chloride ◽  
Oculopharyngeal Muscular Dystrophy

Intranuclear inclusions in oculopharyngeal muscular dystrophy among Bukhara Jews

Neurology ◽  
1996 ◽  
Vol 46 (5) ◽  
pp. 1324-1324 ◽  
Author(s):  
S. C. Blumen ◽  
M. Sadeh ◽  
A. D. Korczyn ◽  
A. Rouche ◽  
P. Nisipeanu ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Intranuclear Inclusions

scholarly journals A nuclear localization domain in the hnRNP A1 protein.

1995 ◽  
Vol 129 (3) ◽  
pp. 551-560 ◽  
Author(s):  
H Siomi ◽  
G Dreyfuss
Keyword(s):  
Nuclear Localization ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Motif ◽  
Hnrnp A1 ◽  
Binding Domains ◽  
Rich Domain ◽  
Localization Domain ◽  
Hnrnp Proteins

The heterogeneous nuclear RNP (hnRNP) A1 protein is one of the major pre-mRNA/mRNA binding proteins in eukaryotic cells and one of the most abundant proteins in the nucleus. It is localized to the nucleoplasm and it also shuttles between the nucleus and the cytoplasm. The amino acid sequence of A1 contains two RNP motif RNA-binding domains (RBDs) at the amino terminus and a glycine-rich domain at the carboxyl terminus. This configuration, designated 2x RBD-Gly, is representative of perhaps the largest family of hnRNP proteins. Unlike most nuclear proteins characterized so far, A1 (and most 2x RBD-Gly proteins) does not contain a recognizable nuclear localization signal (NLS). We have found that a segment of ca. 40 amino acids near the carboxyl end of the protein (designated M9) is necessary and sufficient for nuclear localization; attaching this segment to the bacterial protein beta-galactosidase or to pyruvate kinase completely localized these otherwise cytoplasmic proteins to the nucleus. The RBDs and another RNA binding motif found in the glycine-rich domain, the RGG box, are not required for A1 nuclear localization. M9 is a novel type of nuclear localization domain as it does not contain sequences similar to classical basic-type NLS. Interestingly, sequences similar to M9 are found in other nuclear RNA-binding proteins including hnRNP A2.

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.

scholarly journals Nuclear Inclusions in Oculopharyngeal Muscular Dystrophy in Quebec

1989 ◽  
Vol 16 (4) ◽  
pp. 446-450 ◽  
Author(s):  
Jean-Pierre Bouchard ◽  
François Gagné ◽  
Fernando M. S. Tomé ◽  
Denis Brunet
Keyword(s):  
Muscular Dystrophy ◽  
Common Disease ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Nuclear Inclusions ◽  
Intranuclear Inclusions ◽  
Reverse Genetic ◽  
Genetic Studies ◽  
The Family ◽  
Biochemical Studies ◽  
Large Families

ABSTRACT:Seven French-Canadian cases of clearcut oculopharyngeal muscular dystrophy (OPMD) had their muscle studied for the presence of intranuclear inclusions, and they were all positive. Inclusions of both “mature” and “immature” types were seen in our material. The presence of such intranuclear structures should be added to the criteria of the clinical picture and the family history for diagnosis of a case and inclusion of a family in further genetic studies. Reverse genetic studies of large families and biochemical studies of these intranuclear structures may help to understand the pathogenesis of this common disease in Quebec.

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.

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