title: A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy.
abstract: Ullrich congenital muscular dystrophy (UCMD) is a severe disorder caused, in most cases, by a deficiency in collagen VI microfibrils. Recessive mutations in two of the three collagen VI genes, COL6A2 and COL6A3, have been identified in eight of the nine UCMD patients reported thus far. A heterozygous COL6A1 gene deletion, resulting in a mutant protein that exerts a dominant negative effect, has recently been described in a severely affected UCMD patient. Here we describe a patient in whom reverse transcription-PCR analysis of fibroblast RNA suggested a heterozygous in-frame deletion of exon 13 in the triple-helical domain of COL6A2, which is predicted to be dominantly acting. However, a homozygous A --> G mutation at -10 of intron 12 was found in the genomic DNA. The intron mutation activated numerous cryptic splice acceptor sites, generating normal and exon 13-deleted COL6A2 mRNA, and multiple aberrant transcripts containing frameshifts that were degraded through a nonsense-mediated decay mechanism. Northern analysis indicated diminished COL6A2 mRNA expression as the primary pathogenic mechanism in this UCMD patient. Our results underscore the importance of multifaceted analyses in the accurate molecular diagnosis and interpretation of genotype-phenotype correlations of UCMD.
authors.affiliation: Department of Medical and Surgical Critical Care and Center of Research, Transfer and High Education, MCIDNENT, University of Florence, viale Morgagni 85, 50134 Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lucarini
authors.forename: Betti
authors.initials: B
authors.lastname: Giusti
authors.forename: Rui-Zhu
authors.initials: RZ
authors.lastname: Zhang
authors.forename: Te-Cheng
authors.initials: TC
authors.lastname: Pan
authors.forename: Cecilia
authors.initials: C
authors.lastname: Jimenez-Mallebrera
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mercuri
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Guglielmina
authors.initials: G
authors.lastname: Pepe
authors.forename: Mon-Li
authors.initials: ML
authors.lastname: Chu
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D024142:Collagen Type VI / Q000235:genetics*; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D012326:RNA Splicing / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C504344:COL6A2 protein, human; D024142:Collagen Type VI