Identification and characterization of novel collagen VI non-canonical splicing mutations causing ullrich congenital muscular dystrophy

Elena Martoni, Anna Urciuolo, Patrizia Sabatelli, Marina Fabris, Matteo Bovolenta, Marcella Neri, Paolo Grumati, Adele D'Amico, Marika Pane, Eugenio Mercuri, Enrico Bertini, Luciano Merlini, Paolo Bonaldo, Alessandra Ferlini, Francesca Gualandi

Research output: Contribution to journalArticle

Abstract

Splicing mutations occurring outside the invariant GT and AG dinucleotides are frequent in disease genes and the definition of their pathogenic potential is often challenging. We have identified four patients affected by Ullrich congenital muscular dystrophy and carrying unusual mutations of COL6 genes affecting RNA splicing. In three cases the mutations occurred in the COL6A2 gene and consisted of nucleotide substitutions within the degenerated sequences flanking the canonical dinucleotides. In the fourth case, a genomic deletion occurred which removed the exon8-intron8 junction of the COL6A1 gene. These mutations induced variable splicing phenotypes, consisting of exon skipping, intron retention and cryptic splice site activation/usage. A quantitative RNA assay revealed a reduced level of transcription of the mutated in-frame mRNA originating from a COL6A2 point mutation at intronic position +3. At variance, the transcription level of the mutated in-frame mRNA originating from a genomic deletion which removed the splicing sequences of COL6A1 exon 8 was normal. These findings suggest a different transcriptional efficiency of a regulatory splicing mutation compared to a genomic deletion causing a splicing defect.

Original languageEnglish
JournalHuman Mutation
Volume30
Issue number5
DOIs
Publication statusPublished - May 2009

Keywords

  • COL6A1
  • COL6A2
  • Collagen vi
  • Non-canonical splicing mutations
  • Ullrich congenital muscular dystrophy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Martoni, E., Urciuolo, A., Sabatelli, P., Fabris, M., Bovolenta, M., Neri, M., Grumati, P., D'Amico, A., Pane, M., Mercuri, E., Bertini, E., Merlini, L., Bonaldo, P., Ferlini, A., & Gualandi, F. (2009). Identification and characterization of novel collagen VI non-canonical splicing mutations causing ullrich congenital muscular dystrophy. Human Mutation, 30(5). https://doi.org/10.1002/humu.21022