A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy.
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.
Lucarini
Laura
L
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.
Giusti
Betti
B
Zhang
Rui-Zhu
RZ
Pan
Te-Cheng
TC
Jimenez-Mallebrera
Cecilia
C
Mercuri
Eugenio
E
Muntoni
Francesco
F
Pepe
Guglielmina
G
Chu
Mon-Li
ML
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
C504344:COL6A2 protein, human; D024142:Collagen Type VI