Multiple correcting COL17A1 mutations in patients with revertant mosaicism of epidermolysis bullosa

Am J Hum Genet. 2005 Nov;77(5):727-40. doi: 10.1086/497344. Epub 2005 Sep 9.

Abstract

Revertant mosaicism by somatic reversion of inherited mutations has been described for a number of genetic diseases. Several mechanisms can underlie this reversion process, such as gene conversion, crossing-over, true back mutation, and second-site mutation. Here, we report the occurrence of multiple corrections in two unrelated probands with revertant mosaicism of non-Herlitz junctional epidermolysis bullosa, an autosomal recessive genodermatosis due to mutations in the COL17A1 gene. Immunofluorescence microscopy and laser dissection microscopy, followed by DNA and RNA analysis, were performed on skin biopsy specimens. In patient 1, a true back mutation, 3781T-->C, was identified in the specimen from the arm, and a second-site mutation, 4463-1G-->A, which compensated for the frameshift caused by the inherited 4424-5insC mutation, was identified in the 3' splice site of exon 55 in a specimen from the middle finger. Patient 2 showed--besides two distinct gene conversion events in specimens from the arm and hand sites, both of which corrected the 1706delA mutation--a second-site mutation (3782G-->C) in an ankle specimen, which prevented the premature ending of the protein by the 3781C-->T nonsense mutation (R1226X). Thus, both inherited mutations, paternal as well as maternal, reverted at least once by different reversion events in distinct cell clusters in the described patients. The occurrence of multiple correcting mutations within the same patient indicates that in vivo reversion is less unusual than was generally thought. Furthermore, in the male patient, mosaic patterns of type XVII collagen-positive keratinocytes were present in clinically unaffected and affected skin. This latter observation makes it likely that reversion may be overlooked and may happen more often than expected.

MeSH terms

  • Aged
  • Autoantigens / genetics*
  • Autoantigens / physiology
  • Epidermolysis Bullosa / genetics*
  • Epidermolysis Bullosa / pathology
  • Female
  • Gene Conversion*
  • Humans
  • Male
  • Microscopy, Confocal
  • Middle Aged
  • Mutation
  • Non-Fibrillar Collagens / genetics*
  • Non-Fibrillar Collagens / physiology
  • Sequence Analysis, DNA
  • Skin / pathology

Substances

  • Autoantigens
  • Non-Fibrillar Collagens
  • collagen type XVII