title: Identification and characterization of novel collagen VI non-canonical splicing mutations causing Ullrich congenital muscular dystrophy.
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.
authors.affiliation: Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Martoni
authors.forename: Anna
authors.initials: A
authors.lastname: Urciuolo
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
authors.forename: Marina
authors.initials: M
authors.lastname: Fabris
authors.forename: Matteo
authors.initials: M
authors.lastname: Bovolenta
authors.forename: Marcella
authors.initials: M
authors.lastname: Neri
authors.forename: Paolo
authors.initials: P
authors.lastname: Grumati
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
authors.forename: Marika
authors.initials: M
authors.lastname: Pane
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mercuri
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferlini
authors.forename: Francesca
authors.initials: F
authors.lastname: Gualandi
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D024142:Collagen Type VI / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006579:Heterozygote; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D007438:Introns / Q000235:genetics; D008297:Male; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: C504344:COL6A2 protein, human; D018389:Codon, Nonsense; D024142:Collagen Type VI; D012333:RNA, Messenger