The phenotypic and genotypic features of Chinese patients with oculopharyngeal muscular dystrophy

Abstract

Objective: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset inherited neuromuscular disorder, with progressive ptosis and dysphagia as common manifestations. To date, OPMD has rarely been reported among East Asians. The present study summarizes the phenotypic and genotypic features of Chinese patients with OPMD. Methods: Twenty-one patients with molecularly confirmed OPMD from 9 unrelated families were identified by direct sequencing of the polyadenlyate binding protein nuclear-1 (PABPN1) gene. Immunofluorescence staining of muscle biopsies was conducted to identify the components of protein degradation pathways involved in OPMD. Results: In our cohort, the genetically confirmed OPMD group had a mean age at onset of 50.6 AE 4.2 years (range 45-60 years). Ptosis (42.9%) was the most common initial symptom; patients with ptosis as the first symptom subsequently developed dysphagia within a median time of 5.5 years (range 1-19 years). Evidence of external ophthalmoplegia was found in 38.1% of patients. A total of 33.3% of the patients developed muscle weakness at a median age at onset of 66 years (range 50-70 years), with neck flexor involvement in all patients. Five genotypes were observed in our cohort, including classical (GCG)9-11 repeats in 7 families and non-GCG elongations with additional GCA expansions in 2 families. OPMD muscle biopsies revealed rimmed vacuoles and intranuclear filamentous inclusions. The PABPN1 protein showed substantial accumulation in the nuclei of muscle fiber aggregates and closely colocalized with p62, LC3B and FK2. Interpretation: Our findings indicate wide genetic heterogeneity in OPMD in the Chinese population and demonstrate abnormalities in protein degradation pathways in this disease.

PABPN1 aggregation is driven by Ala expansion and poly(A)-RNA binding, leading to CFIm25 sequestration that impairs alternative polyadenylation

“…OPMD is an orphan disease and the patient specimens are rare. According to the statistics, only 0.1 ∼ 1: 100,000 occurs in the higher-incidence European population, which results in few researches on the PABPN1 aggregates ( 62 ). It is generally acknowledged that the 17A variant could form insoluble aggregates in OPMD patients or mouse models, but at least in cultured cells even in muscle cells, our data suggest that the 17A variant is similar with normal PABPN1 in phase behaviors.…”

Protein Aggregates and Aggrephagy in Myopathies

“…In a cohort of 21 Chinese patients clinically affected by OPMD and genetically characterized by five different pathological genotypes, Lin and colleagues investigated the involvement of the autophagy pathway, focusing on the physical association between PABPN1 and p62, NBR1, LC3 and the ubiquitinated protein marker FK2 [186]. In two patients' muscle biopsies, the authors identified abnormal accumulation of PABPN1 present in 5-7% of the muscle fibers, which were also stained positive for p62, NBR1 and FK2 and, to a lesser extent, LC3.…”