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Antisense-induced messenger depletion corrects a COL6A2 dominant mutation in Ullrich myopathy.

ABSTRACT: Collagen VI gene mutations cause Ullrich and Bethlem muscular dystrophies. Pathogenic mutations frequently have a dominant negative effect, with defects in collagen VI chain secretion and assembly. It is agreed that, conversely, collagen VI haploinsufficiency has no pathological consequences. Thus, RNA-targeting approaches aimed at preferentially inactivating the mutated COL6 messenger may represent a promising therapeutic strategy. By in vitro studies we obtained the preferential depletion of the mutated COL6A2 messenger, by targeting a common single-nucleotide polymorphism (SNP), cistronic with a dominant COL6A2 mutation. We used a 2'-O-methyl phosphorothioate (2'OMePS) antisense oligonucleotide covering the SNP within exon 3, which is out of frame. Exon 3 skipping has the effect of depleting the mutated transcript via RNA nonsense-mediated decay, recovering the correct collagen VI secretion and restoring the ability to form an interconnected microfilament network into the extracellular matrix. This novel RNA modulation approach to correcting dominant mutations may represent a therapeutic strategy potentially applicable to a great variety of mutations and diseases.

SUBMITTER: Gualandi F

PROVIDER: S-EPMC3523246 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Antisense-induced messenger depletion corrects a COL6A2 dominant mutation in Ullrich myopathy.

Gualandi Francesca F Manzati Elisa E Sabatelli Patrizia P Passarelli Chiara C Bovolenta Matteo M Pellegrini Camilla C Perrone Daniela D Squarzoni Stefano S Pegoraro Elena E Bonaldo Paolo P Ferlini Alessandra A

Human gene therapy 20121106 12

Collagen VI gene mutations cause Ullrich and Bethlem muscular dystrophies. Pathogenic mutations frequently have a dominant negative effect, with defects in collagen VI chain secretion and assembly. It is agreed that, conversely, collagen VI haploinsufficiency has no pathological consequences. Thus, RNA-targeting approaches aimed at preferentially inactivating the mutated COL6 messenger may represent a promising therapeutic strategy. By in vitro studies we obtained the preferential depletion of t ...[more]

PMID: 22992134

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Project description:Mutations in the gene encoding type VI collagen cause Bethlem myopathy (MIM 158810) and Ullrich congenital muscular dystrophy (MIM 254090); 2 diseases previously recognized as completely independent, and have been increasingly recognized. However, collagen-related myopathy caused by intron variation in the COL6 gene is rarely reported in China. Ullrich congenital muscular dystrophy is an autosomal recessive disorder that leads to severe muscle weakness with early onset. Thus, children may never walk independently, with proximal joint contractures and significant hyperelastic distal joints, and have early respiratory failure. Therefore, timely diagnosis and treatment are important. We report a spontaneous mutation in the COL6A2 gene causing Ullrich congenital muscular dystrophy type 1 in a pediatric patient. A boy aged 4 years was unable to walk independently, could sit alone for a short time, and his motor development was delayed and had regressed after 1 year of age. He had a high palatal arch and a through palm with localized transverse lines running laterally from the palm. Electromyography showed an impaired neurogenic source, and whole-exon gene sequencing revealed a spontaneous heterozygous mutation in the COL6A2 gene (c.955-2A>G), which was determined to be a pathogenic mutation according to the American Guidelines of the College of Medical Genetics. This child has a delayed motor development, high osprey arch and a through palm with localized transverse lines running laterally from the palm, and regression of motor development after the age of 1 year. Whole exon examination showed spontaneous mutation of the COL6A2 gene; thus, the child was diagnosed with UCMD type 1. At present, there is no special treatment for this disease, and treatment is mainly symptomatic and supportive. The child underwent home massage, rehabilitation training, oral folic acid tablets, vitamins and coenzyme Q10. During the subsequent follow-up period, the patient can now sit alone for a short period of time. We report a case of spontaneous mutation in the COL6A2 gene causing Ullrich congenital muscular dystrophy type 1 in a pediatric patient, expanding the phenotypic spectrum of the disease and enriching the human gene pool.

Dataset Information

Antisense-induced messenger depletion corrects a COL6A2 dominant mutation in Ullrich myopathy.

Publications

Antisense-induced messenger depletion corrects a COL6A2 dominant mutation in Ullrich myopathy.

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