Oculopharyngeal Muscular Dystrophy (PABPN1)
| Dred_ID | RD00017 |
| OMIM ID | 164300 |
| Disease name | Oculopharyngeal Muscular Dystrophy |
| Alternative names | Muscular Dystrophy, Oculopharyngeal Opmd |
| Category | Genetic diseases, Rare diseases, Neuronal diseases, Eye diseases, Muscle diseases |
| Phenotype | NIH Rare Diseases: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder characterized by slowly progressing muscle disease (myopathy) affecting the muscles of the upper eyelids and the throat. Onset is typically during adulthood, most often between 40 and 60 years of age. Symptoms may include: eyelid drooping (ptosis), arm and leg weakness, and difficulty swallowing (dysphagia). There are two types of OPMD, distinguished by their patterns of inheritance. They are known as the autosomal dominant and autosomal recessive types. Both types are caused by mutations in the PABPN1 gene.Treatment depends on the signs and symptoms present in each individual. Ptosis and dysphagia can be managed with surgery; however, recurrence of symptoms commonly occurs 5-15 years after intervention.
OMIM: Oculopharyngeal muscular dystrophy (OPMD) is characterized by ptosis and swallowing difficulties due to selective involvement of the muscles of the eyelid and pharynx, respectively. The mean age of onset of ptosis is usually 48 years and onset of dysphagia is 50 years. Early symptoms of dysphagia are increased time needed to consume a meal and an acquired avoidance of dry foods. Swallowing difficulties determine prognosis, and increase the risk for potentially life-threatening aspiration pneumonia and poor nutrition. |
| Miscellaneouse | OMIM: progressive disorder late-adult onset (fifth to sixth decade) autosomal recessive inheritance has been reported carrier frequency 1:1,000 in french-canadians in quebec carrier frequency 1:200,000 in france carrier frequency 1:700 in bukhara jewish populations |
| Prevalence | Prevalence: >1/1000,1-9/1000000 (United Kingdom),1-9/100000 (Europe) [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | PABPN1 |
| Alias symbols | OPMD; PAB2; PABII; PABP2; PABP-2 |
| Gene name | poly(A) binding protein, nuclear 1 |
| Gene map locus | 14q11.2; chr14:23,321,457-23,326,163(+) |
| Ensembl Gene ID | ENSG00000100836 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | This gene encodes an abundant nuclear protein that binds with high affinity to nascent poly(A) tails. The protein is required for progressive and efficient polymerization of poly(A) tails at the 3' ends of eukaryotic transcripts and controls the size of the poly(A) tail to about 250 nt. At steady-state, this protein is localized in the nucleus whereas a different poly(A) binding protein is localized in the cytoplasm. This gene contains a GCG trinucleotide repeat at the 5' end of the coding region, and expansion of this repeat from the normal 6 copies to 8-13 copies leads to autosomal dominant oculopharyngeal muscular dystrophy (OPMD) disease. Related pseudogenes have been identified on chromosomes 19 and X. Read-through transcription also exists between this gene and the neighboring upstream BCL2-like 2 (BCL2L2) gene. [provided by RefSeq, Dec 2010] |
| Repeat unit | GCG |
| Normal repeat copies | 6-10 |
| Pathogenic repeat copies | ≥12 |
| Gene | PABPN1 |
| Repeat location | CDS |
| Chromosome locus | chr14:23321473-23321505 (+) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | Protein |
| Possible toxicity | PABPN1 is thought to have a pathogenic expanded polyalanine domain with physical characteristics that cause it to accumulate and interfere with normal cellular processes. However, despite the growing number of studies exploring OPMD pathogenesis, the nature of the underlying pathologic mechanism has yet to be established. More generally, there are suggestions that in addition to having a gain-of-function toxic effect, OPMD aggregates could sequester RNA and proteins including PABPN1 essential for proper cellular function.
Using both immunoelectron microscopy and fluorescence confocal microscopy, Calado et al. (2000) determined that the OPMD-specific nuclear inclusions were stained anti-PABP2 antibodies. In addition, the inclusions were labeled with antibodies directed against ubiquitin (see 191339) and the subunits of the proteasome, and contained a less soluble form of PABP2 as well as poly(A) RNA. The authors suggested that the polyalanine expansions in PABP2 induce a misfolding and aggregation of the protein into insoluble inclusions, similarly to events in neurodegenerative diseases caused by CAG/polyglutamine expansions, and that in OPMD the polyalanine expansions in the PABP2 protein may interfere with the cellular traffic of poly(A) RNA. [By OMIM] |
| Pathway annotation | Reactome, KEGG |
| PMID | 22519734 |
| Authors | Bhattacharjee RB, Zannat T, Bag J |
| Title | Expression of the polyalanine expansion mutant of nuclear poly(A)-binding protein induces apoptosis via the p53 pathway |
| Journal | Cell Biol Int. 36(8):697-704 |
| Year | 2012 |
| PMID | 23166521 |
| Authors | Beaulieu YB, Kleinman CL, Landry-Voyer AM, Majewski J, Bachand F |
| Title | Polyadenylation-dependent control of long noncoding RNA expression by the poly(A)-binding protein nuclear 1 |
| Journal | PLoS Genet. 8(11):e1003078 |
| Year | 2012 |