Oculopharyngeal muscular dystrophy: A polyalanine myopathy

Abstract

It has been 10 years since the identification of the first PABPN1 gene (GCN)(n)/polyalanine mutations responsible for oculopharyngeal muscular dystrophy (OPMD). These mutations have been found in most cases of OPMD diagnosed in more than 35 countries. Sequence analyses have shown that such mutations have occurred numerous times in human history. Although PABPN1 was found early on to be a component of the classic filamentous intranuclear inclusions (INIs), mRNA and other proteins also have been found to coaggregate in the INIs. It is still unclear if the INIs play a pathologic or a protective role. The generation of numerous cell and animal models of OPMD has led to greater insight into its complex molecular pathophysiology and identified the first candidate therapeutic molecules. This paper reviews basic and clinical research on OPMD, with special emphasis on recent developments in the understanding of its pathophysiology.

Regulated Intron Retention and Nuclear Pre-mRNA Decay Contribute to PABPN1 Autoregulation

“…Notably, mutations in the PABPN1 gene result in oculopharyngeal muscular dystrophy (OPMD), a lateonset disorder that is associated primarily with eyelids drooping, swallowing difficulties, and proximal limb weakness (10). OPMD mutations have been reported in more than 35 countries (11) and result in a PABPN1 protein with a slightly extended polyalanine tract, a consequence of short trinucleotide expansions in the PABPN1 coding sequence (12). Although the mechanism by which short GCG insertions in the PABPN1 gene cause OPMD remains unknown, altered PABPN1 mRNA levels were found in muscle biopsy specimens of OPMD patients relative to those of age-matched controls (13,14).…”

Modeling Oculopharyngeal Muscular Dystrophy in Myotube Cultures Reveals Reduced Accumulation of Soluble Mutant PABPN1 Protein

“…[17][18][19][20] In these animal model systems, anti-aggregation treatments reduced muscle symptoms and INI formation 19,21,22 ; how-ever, the molecular mechanisms by which expPABPN1 is toxic to cells have not been fully elucidated. Increased frequency of cell death is found in animal and cellular models with expPABPN1 overexpression, 9 but cell death and overexpression of expPABPN1 have not been reported in heterozygous patients with OPMD.…”

“…23 In humans, muscle atrophy was reported in rare homozygous patients, 24 whereas in heterozygous patients, muscle atrophy is not a common pathological characteristic of the disease in its early stages. 18 In a mouse model with low and constitutive expPABPN1 expression, only minor muscle defects were reported without obvious muscle atrophy. 25 Because PABPN1 plays an essential role in diverse cellular functions, such as proliferation and differentiation, manipulating PABPN1 expression beyond physiological concentrations can cause myogenic defects, 26 -28 which may not be reflective of OPMD pathophysiological features.…”

Not Just Another Aspiration Pneumonia: Oculopharyngeal Muscular Dystrophy

“…OPMD is a rare form of genetic muscular dystrophy which is inherited mostly as autosomal dominant and rarely as an autosomal recessive disorder. OPMD is characterized by ocular and pharyngeal muscle involvement, and it commonly presents with adulthood onset ptosis, dysphagia and proximal muscle weakness in advanced cases along with a positive family history of ptosis and dysphagia [1,2,4]. Our patient had all the classic clinical features of OPMD, with positive family history along with proximal muscle weakness in upper extremity which points towards advance stage of disease but was not diagnosed until late as OPMD is easily overlooked and underdiagnosed.…”

“…Unique tubulofilamentous intranuclear inclusions are seen in muscle biopsy [4,5]. Currently, treatment is supportive as no therapeutic intervention is currently available for patients with OPMD.…”