Second Chances for Skin: Correcting Genetic Mutations

      It has been said that “nature finds a way,” and, seemingly, so does skin. Epidermolysis bullosa is a family of genetic skin defects that results in a spectrum of mechanobullous diseases. These diseases impair the quality of life of patients and their families and, in some instances, affect the life span of the patients (
      • Fine J.D.
      Inherited epidermolysis bullosa: recent basic and clinical advances.
      ). A variety of gene defects in critical proteins, including type XVII collagen (encoded by COL17A1), result in skin fragility. Although all skin should be affected by these genetic changes, normal areas of skin are often present clinically, often in areas that previously exhibited blisters. A process called “revertant mosaicism” is thought to cause such normal skin areas. This process may be the consequence of additional genetic changes in select cells (or in select areas of skin), leading to a normalization of the patient's phenotype (
      • Kvittingen E.A.
      • Rootwelt H.
      • Berger R.
      • et al.
      Self-induced correction of the genetic defect in tyrosinemia type I.
      • Lai-Cheong J.E.
      • McGrath J.A.
      • Uitto J.
      Revertant mosaicism in skin: natural gene therapy.
      Based on clinical observations of normal skin at previous sites of blisters in patients with generalized non-Herlitz junctional epidermolysis bullosa,
      • Pasmooij A.M.G.
      • Nijenhuis M.
      • Brander R.
      • et al.
      Natural gene therapy may occur in all patients with generalized non-Herlitz junctional epidermolysis bullosa with COL17A1 mutations.
      , as reported in this issue, studied several patients with this condition to determine whether correction of genetic defects had occurred. These studies employed biopsy of clinically healthy and clinically affected skin in combination with immunofluorescence microscopy, electron microscopy, and laser dissection microscopy to compare tissue and cells from differentially affected skin. The researchers found in vivo reversion of the COL17A1 mutation in the four patients who were examined. A variety of mutations that involved different mechanisms, including mutations affecting gene splicing, were found. Through the following questions, we examine this paper in greater detail. For brief answers, please refer to the supplementary information onlgeneralized non-Herlitz junctionaline


      • Describe generalized non-Herlitz junctional epidermolysis bullosa.
      • What is revertant mosaicism?
      • How did the investigators carry out their study?
      • What were the results and conclusions?
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