Alternative titles; symbols
HGNC Approved Gene Symbol: PABPN1
SNOMEDCT: 77097004; ICD10CM: G71.09;
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38): 14:23,321,457-23,326,163 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q11.2 | Oculopharyngeal muscular dystrophy | 164300 | Autosomal dominant | 3 |
By positional cloning for a candidate gene mutant in oculopharyngeal muscular dystrophy (OPMD; 164300), which maps to chromosome 14q11, Brais et al. (1998) isolated PABPN1, which they called PABP2. PABP2 is homologous to the bovine poly(A)-binding protein-2 gene. Northern blot analysis suggested multiple splice variants.
Brais et al. (1998) determined that the PABPN1 gene contains 7 exons.
Fan et al. (2001) reported that oligomerization of PABPN1 is mediated by 2 potential oligomerization domains. Inactivating oligomerization of mutated PABPN1 by deletions of 6 to 8 amino acids in either of the oligomerization domains prevented nuclear protein aggregation and significantly reduced cell death in a cell transfection model. The authors concluded that oligomerization of PABPN1 may play a crucial role in the formation of OPMD nuclear protein aggregation, and that the expanded polyalanine stretch is necessary but not sufficient to induce OPMD protein aggregation.
Kim et al. (2001) established stable mouse skeletal muscle C2 cell lines expressing human PABP2. The cells showed morphologically enhanced myotube formation accompanied by an increased transcription of myogenic factors MyoD (159970) and myogenin (159980). Using a yeast 2-hybrid system, ski-interacting protein (SKIP; 603055) was shown to bind to PABP2. Immunofluorescence studies showed that PABP2 colocalized with SKIP in nuclear speckles. Reporter assays showed that PABP2 cooperated with SKIP to activate synergistically E-box-mediated transcription through MyoD. Moreover, both PABP2 and SKIP were directly associated with MyoD to form a single complex. The authors suggested that PABP2 and SKIP directly control the expression of muscle-specific genes at the transcriptional level.
Abu-Baker et al. (2003) reported that protein aggregation in a transient transfection cell model of OPMD directly impaired the function of the ubiquitin-proteasome pathway (UPP) as well as molecular chaperone functions. The proteasome inhibitor lactacystin caused significant increase of protein aggregation and toxicity. Overexpression of molecular chaperones HSP40 (DNAJB1; 604572) and HSP70 (see 140559) suppressed protein aggregation and toxicity, and aggregation of mutated PABPN1 protein carrying a polyalanine expansion (PABPN1-ala17) proportionally correlated with toxicity. Coexpression of chaperones in this cell model increased the solubility of PABPN1-ala17 and the rate of transfected cell survival.
Berciano et al. (2004) reported the presence of intranuclear inclusions composed of tubular filaments in oxytocin (167050)-producing neurons from normal rat hypothalamus. Like OPMD inclusions, the filamentous structures in neurosecretory neurons accumulated PABPN1, poly(A) RNA, ubiquitin (see 191339), and proteasomes. These inclusions did not contain members of the HSP40 and HDJ2/DNAJ families of chaperones. The proportion of oxytocin-producing neurons that contained inclusions decreased during parturition and lactation, when synthesis and release of oxytocin is maximal, and increased at 1 day post-weaning, when a drastic reduction in the production of the hormone occurs. The authors concluded that PABPN1 filaments in normal neurons are dynamic structures, the appearance of which correlates with changes in cellular activity.
Apponi et al. (2010) examined the effects of Pabpn1 depletion using siRNA in primary mouse myoblasts from extraocular, pharyngeal, and limb muscles. Pabpn1 knockdown significantly decreased cell proliferation and myoblast differentiation during myogenesis in vitro. Pabpn1 depletion in myoblasts led to a shortening of mRNA poly(A) tails, demonstrating the cellular function of PABPN1 in polyadenylation control in a mammalian cell. Pabpn1 depletion also caused nuclear accumulation of poly(A) RNA, revealing that PABPN1 is required for proper poly(A) RNA export from the nucleus. The authors concluded that PABPN1 plays an essential role in myoblast proliferation and differentiation, and suggested that it is required for muscle regeneration and maintenance in vivo.
In patients with oculopharyngeal muscular dystrophy-1 (OPMD1; 164300), Brais et al. (1998) identified short N-terminal trinucleotide expansions (GCG) in the PABP2 gene (602279.0001). A wildtype (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in affected members from each of 144 OPMD families screened. A (GCG)7 allele (602279.0002) was found in 2% of the population, consistent with a polymorphism. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele, whereas homozygosity for the (GCG)7 allele led to OPMD. Brais et al. (1998) noted that the (GCG)7 allele is an example of a polymorphism that can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathologic expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.
Brais et al. (1998) estimated the meiotic stability of the (GCG)9 repeat. Seventy of the 71 French Canadian OPMD families tested to that time segregated a (GCG)9 expansion. However, in 1 family, the affected brother and sister, despite sharing the French Canadian ancestral haplotype, carried a (GCG)12 expansion, including twice the number of abnormal GCG repeats as the ancestral (GCG)9 mutation. The authors estimated that 450 historic meioses shaped the 123 OPMD cases belonging to 42 of the 71 enrolled families. Screening the full set of participants allowed them to identify another 148 (GCG)9 carrier chromosomes, and they estimated that a single mutation of the (GCG)9 expansion had occurred in 598 meioses.
Another example of pathologic expansion of short trinucleotide repeats had been observed in the case of the gene encoding cartilage oligomeric matrix protein (COMP; 600310), in which the common (GAC)5 repeat, encoding a polyaspartate tract, was associated with either pseudoachondroplastic dysplasia (177170) or multiple epiphyseal dysplasia (132400) (Delot et al., 1999).
In 2 unrelated Japanese patients with OPMD, Nakamoto et al. (2002) identified 2 expansions in the PABP2 gene: a 12-bp elongation and a 15-bp elongation. Both sequences could be explained by the insertions or duplications of (GCG)3(GCA) and (GCG)2(GCA)3, respectively, into the normal sequence. The number of encoded alanine residues increased from the normal 10 to pathologic 14 in the first patient and his affected sister, and from 10 to 15 in the second patient. Nakamoto et al. (2002) suggested that the mutations resulted from unequal crossing over during germ cell homologous recombination, rather than from DNA slippage. Similarly, expansion mutation in the HOXD13 gene (142989) has been explained by unequal crossing over.
Mezei et al. (1999) did not observe any expansions in the PABP2 gene in 22 sporadic or 3 familial cases of inclusion body myositis (147421), which shares histologic characteristics with some advanced cases of oculopharyngeal dystrophy.
Robinson et al. (2005) analyzed the PABPN1 gene expansion sequence in 86 patients with OPMD and found 13 different expansion types. The expansions were stable through meiosis and mitosis, suggesting a different mechanism of mutation from that of most other triplet repeat mutations. Most reports described OPMD expansions as consisting of multiples of a GCG sequence. However, some studies detected GCA interspersions. Robinson et al. (2005) found that 6 of the different types of expansion mutation contained GCA and GCG, and almost all of these were consistent with a mutational mechanism of unequal recombination.
In a woman with OPMD, Robinson et al. (2006) identified a heterozygous missense mutation in the PABPN1 gene (G12A; 602279.0003) that generated a contiguous sequence of 13 alanine codons, which is causative of disease in the common triplet repeat expansion mutation. The woman had disease onset at age 61 years and reported 5 affected family members.
Hino et al. (2004) generated transgenic mice expressing the human PABPN1 gene. Transgenic mice lines expressing normal PABPN1 with a 10-alanine stretch did not reveal myopathic changes, whereas lines expressing high levels of expanded PABPN1 with a 13-alanine stretch showed an apparent myopathy phenotype, especially in old age. Pathologic studies in the latter mice disclosed intranuclear inclusions consisting of aggregated mutant human PABPN1 product. Some TUNEL-positive nuclei were shown around degenerating fibers and in a cluster in the lesion in necrotic muscle fibers. The degree of myopathic change was more prominent in eyelid and pharyngeal muscles, and muscle weakness in limbs was apparent from the fatigability test. Nuclear inclusions seemed to develop gradually with aging, at least after 1 week of age, in transgenic mouse muscles.
Catoire et al. (2008) found that expression of human PABPN1 containing 13 alanines resulted in muscle cell degeneration and abnormal motility in transgenic nematodes. Increased expression of Sirt1 (604479) exacerbated muscle pathology, an effect that depended on Foxo (see FOXO1A; 136533) and Ampk (see PRKAA1; 602739), whereas null mutants of Sirt1 and Ampk were protective.
Davies et al. (2008) demonstrated that overexpression of wildtype PABPN1 reduced cellular toxicity of 17(GCG)-repeat PABPN1 in both COS-7 cells and in a mouse model of OPMD and that the effect was independent of aggregation of the expanded mutant protein. Wildtype PABPN1 also provided some protection to cells against proapoptotic insults distinct from the OPMD mutation, such as staurosporine treatment and Bax expression. Conversely, knockdown of PABPN1, which itself was not toxic, made cells more susceptible to apoptotic stimuli. The protective effect of wildtype PABPN1 was mediated by its regulation of XIAP (300079) translation. This normal activity of PABPN1 was partially lost with mutant PABPN1, such that elevated levels of XIAP were seen in mice expressing wildtype, but not mutant PABPN1. These findings indicated that PABPN1 acts as an antiapoptotic factor, and suggested that compromised antiapoptotic function may contribute to the disease mechanism of OPMD.
Trollet et al. (2010) used a transgenic mouse model of OPMD (A17.1) to perform transcriptomic studies combined with a detailed phenotypic characterization of this model at 3 time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which was a significant deregulation of pathways associated with muscle atrophy. One-third of the progressive genes were also associated with muscle atrophy. Functional and histologic analysis of skeletal muscle in this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibers, which contained a large number of intranuclear inclusions. The soleus muscle and, in particular, oxidative fibers, were spared even though they contained intranuclear inclusions, albeit to a lesser degree. The authors concluded that there was a fiber-type specificity of muscle atrophy in this OPMD model.
Brais et al. (1998) found heterozygosity for expansion of a (GCG)6 repeat encoding a polyalanine tract in the PABPN1 gene. In most cases of oculopharyngeal muscular dystrophy-1 (OPMD1; 164300), the (GCG)6 was expanded to (GCG)8-13.
Brais et al. (1998) found a (GCG)7 allele in 2% of the population, consistent with a polymorphism. In compound heterozygous state with the (GCG)9 mutation, a more severe OPMD1 (OPMD1; 164300) phenotype was observed, whereas homozygosity for the (GCG)7 allele also led to OPMD.
In a woman with oculopharyngeal muscular dystrophy (OPMD1; 164300), Robinson et al. (2006) identified a heterozygous c.35G-C transversion in exon 1 of the PABPN1 gene, resulting in a gly12-to-ala (G12A) substitution. The G12A change occurs immediately 3-prime to the normal 10 alanine codon repeat sequence and generates a contiguous sequence of 13 alanine codons, which is causative of disease in the common triplet repeat expansion mutation (602279.0001). The woman had disease onset at age 61 years and reported 5 affected family members.
Abu-Baker, A., Messaed, C., Laganiere, J., Gaspar, C., Brais, B., Rouleau, G. A. Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy. Hum. Molec. Genet. 12: 2609-2623, 2003. [PubMed: 12944420] [Full Text: https://doi.org/10.1093/hmg/ddg293]
Apponi, L. H., Leung, S. W., Williams, K. R., Valentini, S. R., Corbett, A. H., Pavlath, G. K. Loss of nuclear poly(A)-binding protein 1 causes defects in myogenesis and mRNA biogenesis. Hum. Molec. Genet. 19: 1058-1065, 2010. [PubMed: 20035013] [Full Text: https://doi.org/10.1093/hmg/ddp569]
Berciano, M. T., Villagra, N. T., Ojeda, J. L., Navascues, J., Gomes, A., Lafarga, M., Carmo-Fonseca, M. Oculopharyngeal muscular dystrophy-like nuclear inclusions are present in normal magnocellular neurosecretory neurons of the hypothalamus. Hum. Molec. Genet. 13: 829-838, 2004. [PubMed: 14976164] [Full Text: https://doi.org/10.1093/hmg/ddh101]
Brais, B., Bouchard, J.-P., Xie, Y.-G., Rochefort, D. L., Chretien, N., Tome, F. M. S., Lafreniere, R. G., Rommens, J. M., Uyama, E., Nohira, O., Blumen, S., Korczyn, A. D., Heutink, P., Mathieu, J., Duranceau, A., Codere, F., Fardeau, M., Rouleau, G. A. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nature Genet. 18: 164-167, 1998. Note: Erratum: Nature Genet. 19: 404 only, 1998. [PubMed: 9462747] [Full Text: https://doi.org/10.1038/ng0298-164]
Catoire, H., Pasco, M. Y., Abu-Baker, A., Holbert, S., Tourette, C., Brais, B., Rouleau, G. A., Parker, J. A., Neri, C. Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1. Hum. Molec. Genet. 17: 2108-2117, 2008. [PubMed: 18397876] [Full Text: https://doi.org/10.1093/hmg/ddn109]
Davies, J. E., Sarkar, S., Rubinsztein, D. C. Wild-type PABPN1 is anti-apoptotic and reduces toxicity of the oculopharyngeal muscular dystrophy mutation. Hum. Molec. Genet. 17: 1097-1108, 2008. [PubMed: 18178579] [Full Text: https://doi.org/10.1093/hmg/ddm382]
Delot, E., King, L. M., Briggs, M. D., Wilcox, W. R., Cohn, D. H. Trinucleotide expansion mutations in the cartilage oligomeric matrix protein (COMP) gene. Hum. Molec. Genet. 8: 123-128, 1999. [PubMed: 9887340] [Full Text: https://doi.org/10.1093/hmg/8.1.123]
Fan, X., Dion, P., Laganiere, J., Brais, B., Rouleau, G. A. Oligomerization of polyalanine expanded PABPN1 facilitates nuclear protein aggregation that is associated with cell death. Hum. Molec. Genet. 10: 2341-2351, 2001. [PubMed: 11689481] [Full Text: https://doi.org/10.1093/hmg/10.21.2341]
Hino, H., Araki, K., Uyama, E., Takeya, M., Araki, M., Yoshinobu, K., Miike, K., Kawazoe, Y., Maeda, Y., Uchino, M., Yamamura, K. Myopathy phenotype in transgenic mice expressing mutated PABPN1 as a model of oculopharyngeal muscular dystrophy. Hum. Molec. Genet. 13: 181-190, 2004. [PubMed: 14645203] [Full Text: https://doi.org/10.1093/hmg/ddh017]
Kim, Y.-J., Noguchi, S., Hayashi, Y. K., Tsukahara, T., Shimizu, T., Arahata, K. The product of an oculopharyngeal muscular dystrophy gene, poly(A)-binding protein 2, interacts with SKIP and stimulates muscle-specific gene expression. Hum. Molec. Genet. 10: 1129-1139, 2001. [PubMed: 11371506] [Full Text: https://doi.org/10.1093/hmg/10.11.1129]
Mezei, M. M., Mankodi, A., Brais, B., Marineau, C., Thornton, C. A., Rouleau, G. A., Karpati, G. Minimal expansion of the GCG repeat in the PABP2 gene does not predispose to sporadic inclusion body myositis. Neurology 52: 669-670, 1999. [PubMed: 10025815] [Full Text: https://doi.org/10.1212/wnl.52.3.669]
Nakamoto, M., Nakano, S., Kawashima, S., Ihara, M., Nishimura, Y., Shinde, A., Kakizuka, A. Unequal crossing-over in unique PABP2 mutations in Japanese patients: a possible cause of oculopharyngeal muscular dystrophy. Arch. Neurol. 59: 474-477, 2002. [PubMed: 11890856] [Full Text: https://doi.org/10.1001/archneur.59.3.474]
Robinson, D. O., Hammans, S. R., Read, S. P., Sillibourne, J. Oculopharyngeal muscular dystrophy (OPMD): analysis of the PABPN1 gene expansion sequence in 86 patients reveals 13 different expansion types and further evidence for unequal recombination as the mutational mechanism. Hum. Genet. 116: 267-271, 2005. [PubMed: 15645184] [Full Text: https://doi.org/10.1007/s00439-004-1235-2]
Robinson, D. O., Wills, A. J., Hammans, S. R., Read, S. P., Sillibourne, J. Oculopharyngeal muscular dystrophy: a point mutation which mimics the effect of the PABPN1 gene triplet repeat expansion mutation. J. Med. Genet. 43: e23, 2006. Note: Electronic Article. [PubMed: 16648376] [Full Text: https://doi.org/10.1136/jmg.2005.037598]
Trollet, C., Anvar, S. Y., Vanema, A., Hargreaves, I. P., Foster, K., Vignaud, A., Ferry, A., Negroni, E., Hourde, C., Baraibar, M. A., 't Hoen, P. A. C., Davies, J. E., Rubinsztein, D. C., Heales, S. J., Mouly, V., van der Maarel, S. M., Butler-Browne, G., Raz V., Dickson, G. Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres. Hum. Molec. Genet. 19: 2191-2207, 2010. [PubMed: 20207626] [Full Text: https://doi.org/10.1093/hmg/ddq098]