GCG genetic expansions in Italian patients with oculopharyngeal muscular dystrophy

Mirabella, Massimiliano; Silvestri, Gabriella; Rosa, G. De; Giovanni, Simone Di; Muzio, Antonio Di; Uncini, Aurelio; Tonali, P.; Servidei, Serenella

doi:10.1212/wnl.54.3.608

Cited by 49 publications

(41 citation statements)

References 25 publications

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“…In patients from Germany, USA, Israel, UK, Italy and Japan the same mutation has been observed (Muller et al, 2001;Grewal et al, 1999;Blumen et al, 2000;Hill et al, 2001;Mirabella et al, 2000;Nagashima et al, 2000).…”

Section: Introductionmentioning

confidence: 54%

Oculopharyngeal muscular dystrophy (OPMD) due to a small duplication in the PABPN1 gene

2003

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Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant muscle disorder. The OPMD-locus has been mapped to chromosome 14q11.2-q13. The polyadenylate binding protein nuclear 1 (PABPN1; PABP2) gene has been identified as the mutated gene. The mutation consists of a short meiotically stable trinucleotide repeat in the first exon of PABPN1 gene. We have investigated Dutch OPMD patients from four unrelated families and identified a new mutation in two of the four families. Instead of a repeat expansion we found a duplication in the first exon of the PABPN1 gene (c.27_28ins12, p.11_12insAAAA). The identification of this new mutation supports the theory of unequal crossing-over as molecular mechanism causing the mutation in the PABPN1 gene responsible for OPMD, and not the slippage model.

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Section: Introductionmentioning

confidence: 54%

Oculopharyngeal muscular dystrophy (OPMD) due to a small duplication in the PABPN1 gene

2003

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“…It is clear, however, that the severity of the phenotype varies even with carriers of the same size of (GCG) n PABPN1 mutation (Bouchard et al, 1997;Brais et al, 1998a, b). Preliminary studies have not demonstrated whether the size of the mutation influences the severity of the phenotype, at least when assessed by age of onset (Mirabella et al, 2000;Hill et al, 2001;Muller et al, 2001). Only carriers of the smallest (GCG) 8 PABPN1 mutation clearly appear to have a milder phenotype, with a later age of onset in the seventh decade characterized by ptosis and only mild dysphagia (Brais et al, 1998a, b;Hill et al, 2001;Muller et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…This polymorphism has a 1-2 % prevalence in North America, Europe, and Japan. Patients with a more severe compound heterozygote OPMD phenotype have also been observed in Italy and the UK (Mirabella et al, 2000;Hill et al, 2001). The cause of the increased severity in the other 80 % is unknown.…”

Section: Molecular Geneticsmentioning

confidence: 99%

Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease

Brais¹

2003

Cytogenet Genome Res

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Oculopharyngeal muscular dystrophy (OPMD) is a muscle disease of late onset associated with progressive ptosis of the eyelids, dysphagia, and unique tubulofilamentous intranuclear inclusions (INIs). OPMD is usually transmitted as an autosomal dominant trait (OMIM 164300). A rarer allelic autosomal recessive form has also been observed (OMIM 257950). Both forms are caused by short (GCG)_8–13 expansions in the polyadenylate-binding protein nuclear 1 gene (PABPN1) located on chromosome 14q11.1. The mutations cause the lengthening of an N-terminal polyalanine domain. Both slippage and unequal recombination have been proposed as the mutation mechanisms. The size of the mutation has not yet been conclusively shown to inversely correlate with the severity of the phenotype. Mutated PABPN1 proteins have been shown to be constituents of the INIs. The INIs also contain ubiquitin, proteasome subunits, HSP 40, HSP 70, SKIP, and abundant poly(A)-mRNA. The exact mechanism responsible for polyalanine toxicity in OPMD is unknown. Various intranuclear inclusion dependent and independent mechanisms have been proposed based on the major known function of PABPN1 in polyadenylation of mRNA and its shuttling from the nucleus to the cytoplasm. OPMD is one of the few triplet-repeat diseases for which the function of the mutated gene is known. Because of the increasing number of diseases caused by polyalanine expansions and the pathological overlap with CAG/polyglutamine diseases, what pathological insight is gained by the study of OPMD could lead to a better understanding of a much larger group of developmental and degenerative diseases.

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“…These peripheral nerve lesions in OPMD have been reported previously in rare instances. [1][2][3][4][5][6][7][8] Clinical features consistent with denervation in OPMD include hyporeflexia or areflexia, 2,5-7 pes cavus, 2 fasciculations of limbs or tongue muscles, 2 amyotrophy distally in the limbs, 2,7 and distal hypesthesia in lower or upper limbs, often with impaired vibration perception. 2,[4][5][6] Whereas SNAPs and CMAPs were markedly reduced in our case, they are usually normal or slightly reduced in cases of OPMD with PNS involvement.…”

Section: Discussionmentioning

confidence: 99%

“…Although the primary muscular origin of the disease is established, rare cases of peripheral nervous system (PNS) involvement have been described. [1][2][3][4][5][6][7][8] We report the case of a patient with OPMD and PNS involvement. …”

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confidence: 99%

Neurogenic involvement in a case of oculopharyngeal muscular dystrophy

2001

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We report the case of a 65-year-old man with a 15-year history of oculopharyngeal muscular dystrophy (OPMD) harboring a (GCG)11 mutation of the poly(A)-binding protein 2 (PABP2) gene. He developed, early in the course of the disease, a severe chronic axonal neuropathy. Although the primary myopathic origin of the disease appears to be established, a small number of cases of OPMD with neuropathic features have been described. This case raises the question of a possible neurogenic component to this disease and the role of the length of the mutation in phenotype severity.

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GCG genetic expansions in Italian patients with oculopharyngeal muscular dystrophy

Cited by 49 publications

References 25 publications

Oculopharyngeal muscular dystrophy (OPMD) due to a small duplication in the PABPN1 gene

Oculopharyngeal muscular dystrophy (OPMD) due to a small duplication in the PABPN1 gene

Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease

Neurogenic involvement in a case of oculopharyngeal muscular dystrophy

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