Two different PABPN1 expanded alleles in a Mexican population with oculopharyngeal muscular dystrophy arising from independent founder effects

Rivera, David Rincón; Mejia-Lopez, Herlinda; Pompa-Mera, Ericka N.; Villanueva‐Mendoza, Cristina; Nava-Castañeda, Ángel; Garnica–Hayashi, L.; Cuevas-Covarrubias, Sergio A.; Zenteno, Juan Carlos

doi:10.1136/bjo.2007.131482

Cited by 9 publications

(10 citation statements)

References 24 publications

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“…OPMD is an autosomal dominant, late-onset myopathy with a prevalence that varies across different populations. It has been previously shown that there is an increased prevalence of the disease in certain regions which is generally linked to a specific size of the expansion, suggesting a potential founder effect [21][22][23]. Based on our data, we estimate the prevalence of the disease to be at least of 5.65/100,000 habitants in the Canary Islands, which is higher than the prevalence reported in other European regions [16,17].…”

Section: Discussionmentioning

confidence: 56%

“…On the contrary, the estimated prevalence in Europe is about 0.5 to 1 case per 100,000 habitants and it is even lower in some regions like the United Kingdom or Scandinavia [16][17][18][19][20]. The most frequent reported pathologic allele contains 13 repetitions, although in some specific populations other alleles predominate and could even have a founder effect [15,[21][22][23][24]. In this sense, it has been suggested that the large prevalence of OPMD in Uruguay could be related with a migratory move from the Canary Islands in the 19th century [22,25].…”

Section: Introductionmentioning

confidence: 99%

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Clinical and genetic features of a large homogeneous cohort of oculopharyngeal muscular dystrophy patients from the Canary Islands

Alonso‐Pérez

Hernández

Pérez-Pérez

et al. 2022

Euro J of Neurology

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Background Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late‐onset myopathy characterized by ptosis, dysphagia, and progressive proximal limb muscle weakness. The disease is produced by a short expansion of the (GCN)n triplet in the PABPN1 gene. The size of expansion has been correlated to the disease onset and severity. We report the clinical features of a large cohort of OPMD patients harboring the (GCN)15 allele from the Canary Islands. Methods A retrospective observational study was performed analyzing the clinical, demographic, and genetic data of 123 OPMD patients. Clinical data from this cohort were compared with clinical data collected in a large European study including 139 OPMD patients. Results A total of 113 patients (94.2%) carried the (GCN)15 expanded PABN1 allele. Age of symptoms’ onset was 45.1 years. The most frequent symptom at onset was ptosis (85.2%) followed by dysphagia (12%). The severity of the disease was milder in the Canary cohort compared to European patients as limb weakness (35.1% vs. 50.4%), the proportion of patients that require assistance for walking or use a wheelchair (9.3% vs. 27.4%), and needed of surgery because of severe dysphagia (4.6% vs. 22.8%) was higher in the European cohort. Conclusions Nearly 95% of patients with OPMD from the Canary Islands harbored the (GCN)15 expanded allele supporting a potential founder effect. Disease progression seemed to be milder in the (GCN)15 OPMD Canary cohort than in other cohorts with shorter expansions suggesting that other factors, apart from the expansion size, could be involved in the progression of the disease.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Clinical and genetic features of a large homogeneous cohort of oculopharyngeal muscular dystrophy patients from the Canary Islands

Alonso‐Pérez

Hernández

Pérez-Pérez

et al. 2022

Euro J of Neurology

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“…We then searched the literature trying to find any SNP that is associated with the mutated allele. We found four studies reported the presence of specific SNPs that are associated with the polyAla repeat expansion in OPMD32, 33, 34, 35 (Table S3). There are two major limitations of these studies.…”

Section: Resultsmentioning

confidence: 99%

RNA-Based Therapy Utilizing Oculopharyngeal Muscular Dystrophy Transcript Knockdown and Replacement

Abu-Baker

Kharma

Perreault

et al. 2019

Molecular Therapy - Nucleic Acids

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Oculopharyngeal muscular dystrophy (OPMD) is caused by a small expansion of a short polyalanine (polyAla) tract in the poly(A)-binding protein nuclear 1 protein (PABPN1). Despite the monogenic nature of OPMD, no treatment is currently available. Here we report an RNA replacement strategy that has therapeutic potential in cell and C. elegans OPMD models. We develop selective microRNAs (miRNAs) against PABPN1, and we report that miRNAs and our previously developed hammerhead ribozymes (hhRzs) are capable of reducing the expression of both the mRNA and protein levels of PABPN1 by as much as 90%. Since OPMD derives from a very small expansion of GCG within the polyAla tract, our hhRz and miRNA molecules cannot distinguish between the wild-type and mutant mRNAs of PABPN1 . Therefore, we designed an optimized-codon wild-type PABPN1 (opt-PABPN1) that is resistant to cleavage by hhRzs and miRNAs. Co-expression of opt-PABPN1 with either our hhRzs or miRNAs restored the level of PABPN1, concomitantly with a reduction in expanded PABPN1 -associated cell death in a stable C2C12 OPMD model. Interestingly, knockdown of the PABPN1 by selective hhRzs in the C. elegans OPMD model significantly improved the motility of the PABPN1-13Ala worms. Taken together, RNA replacement therapy represents an exciting approach for OPMD treatment.

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“…Our patients reported an onset of ptosis at around 40 years, which has also been described in the Mexican population, where the mean age at onset of ptosis was 46.5 years in subjects with the (GCG) 11 (GCA) 3 GCG (or (GCN) 15 ) mutation, compared with 54.7 years in those with the (GCG) 9 or (GCN) 13 mutation. [13] All patients showed signs of external ophthalmoplegia, which was severe in two cases.…”

Section: Discussionmentioning

confidence: 95%

“…In the Mexican population, the possibility of two independent founder effects has been suggested, since the (GCG) 11 (GCA) 3 GCG (or (GCN) 15 ) and (GCG) 9 or (GCN) 13 mutant alleles both occurred in the investigated patients. [13] Interestingly, in the study from Uruguay, one of the patients was an individual from SA who also carried the (GCG) 11 (GCA) 3 GCG (or (GCN) 15 ) mutation, but no further details on this patient are available.…”

Section: Discussionmentioning

confidence: 99%

A South African family with oculopharyngeal muscular dystrophy: Clinical and molecular genetic characteristics

et al. 2015

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Autosomal dominantly inherited oculopharyngeal muscular dystrophy (OPMD) is caused by a trinucleotide repeat expansion in exon 1 of the polyadenylate binding protein nuclear 1 (PABPN1) gene on chromosome 14q. A large family with OPMD was recently identified in Pretoria, South Africa (SA). Molecular studies revealed a (GCG)11(GCA)3GCG or (GCN)15 mutant allele. The (GCN)15 mutation detected in this family has been described previously in families from Uruguay and Mexico as a founder effect. To our knowledge, this is the first report of an SA Afrikaner family with molecularly confirmed OPMD. The proband, a 64-year-old woman, presented to the neurology outpatient department at Steve Biko Academic Hospital, Pretoria. A sibship of 18 individuals was identified, of whom eight had OPMD. Four patients were interviewed and examined clinically, and electromyographic studies were performed. Molecular analysis of the PABPN1 gene was performed by polymerase chain reaction amplification and direct sequencing of exon 1 in three of the patients. Patients presented with ptosis, external ophthalmoplegia, dysphagia, dysarthria and mild proximal weakness. High foot arches and absent ankle reflexes raised the possibility of peripheral neuropathy, but electromyography showed only mildly low sensory amplitudes, and myopathic units in two patients.

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Two different PABPN1 expanded alleles in a Mexican population with oculopharyngeal muscular dystrophy arising from independent founder effects

Cited by 9 publications

References 24 publications

Clinical and genetic features of a large homogeneous cohort of oculopharyngeal muscular dystrophy patients from the Canary Islands

Clinical and genetic features of a large homogeneous cohort of oculopharyngeal muscular dystrophy patients from the Canary Islands

RNA-Based Therapy Utilizing Oculopharyngeal Muscular Dystrophy Transcript Knockdown and Replacement

A South African family with oculopharyngeal muscular dystrophy: Clinical and molecular genetic characteristics

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