An RNA-mediated toxic gain-of-function has been indicated as the pathogenic mechanism underlying Myotonic dystrophies type 1 and type 2 (DM1 and DM2), two dominantly inherited myopathies with complex phenotypes and involvement of multiple organs. A number of gene transcripts are aberrantly spliced in DM1 and DM2 leading to the expression of foetal isoforms during the adult life. In particular, mutated mRNAs derived from the Troponin T (TnT) genes in striated muscles have been reported. The aim of this work is to demonstrate the abnormal expression of foetal TnT isoforms in adult DM2 human biopsies. PCR-amplified products have been analysed by agarose-gel electrophoresis, and amplicons abnormally migrating, with respect to the controls, have been sequenced. We show here that at least two isoforms derived from the alternative splicing within the hypervariable region of the fast TNNT3 gene still contain the foetal exon. The persistence of the foetal exon has been found both within a full-length isoform not previously described in adults and in association with a shorter sequence derived from alternative splicing in the hypervariable region.

Missplicing of Troponin T transcripts in Myotonic dystrophy type 2 human biopsies

SALVATORI, SERGIO;PICARD, ANNE ALEIDA;FANIN, MARINA;TREVISAN, CARLO PIETRO;ANGELINI, CORRADO
2010

Abstract

An RNA-mediated toxic gain-of-function has been indicated as the pathogenic mechanism underlying Myotonic dystrophies type 1 and type 2 (DM1 and DM2), two dominantly inherited myopathies with complex phenotypes and involvement of multiple organs. A number of gene transcripts are aberrantly spliced in DM1 and DM2 leading to the expression of foetal isoforms during the adult life. In particular, mutated mRNAs derived from the Troponin T (TnT) genes in striated muscles have been reported. The aim of this work is to demonstrate the abnormal expression of foetal TnT isoforms in adult DM2 human biopsies. PCR-amplified products have been analysed by agarose-gel electrophoresis, and amplicons abnormally migrating, with respect to the controls, have been sequenced. We show here that at least two isoforms derived from the alternative splicing within the hypervariable region of the fast TNNT3 gene still contain the foetal exon. The persistence of the foetal exon has been found both within a full-length isoform not previously described in adults and in association with a shorter sequence derived from alternative splicing in the hypervariable region.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/2485282
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