Human Genetics

, Volume 117, Issue 5, pp 460–466

A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy

  • Laura Lucarini
  • Betti Giusti
  • Rui-Zhu Zhang
  • Te-Cheng Pan
  • Cecilia Jimenez-Mallebrera
  • Eugenio Mercuri
  • Francesco Muntoni
  • Guglielmina Pepe
  • Mon-Li Chu
Original Investigation

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.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Laura Lucarini
    • 1
    • 2
  • Betti Giusti
    • 1
  • Rui-Zhu Zhang
    • 2
  • Te-Cheng Pan
    • 2
  • Cecilia Jimenez-Mallebrera
    • 3
  • Eugenio Mercuri
    • 3
  • Francesco Muntoni
    • 3
  • Guglielmina Pepe
    • 1
  • Mon-Li Chu
    • 2
    • 4
  1. 1.Department of Medical and Surgical Critical Care and Center of Research, Transfer and High Education, MCIDNENTUniversity of FlorenceFlorenceItaly
  2. 2.Department of Dermatology and Cutaneous BiologyThomas Jefferson UniversityPhiladelphiaUSA
  3. 3.Dubowitz Neuromuscular Centre, Department of Paediatrics & Neonatal MedicineImperial CollegeLondonUK
  4. 4.Department of Biochemistry and Molecular PharmacologyThomas Jefferson UniversityPhiladelphiaUSA

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