Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination
Dimitra Kiritsi, … , Leena Bruckner-Tuderman, Cristina Has
Dimitra Kiritsi, … , Leena Bruckner-Tuderman, Cristina Has
Published May 1, 2012; First published April 2, 2012
Citation Information: J Clin Invest. 2012;122(5):1742-1746. https://doi.org/10.1172/JCI61976.
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Categories: Brief Report Dermatology

Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination

Abstract

Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.

Authors

Dimitra Kiritsi, Yinghong He, Anna M.G. Pasmooij, Meltem Onder, Rudolf Happle, Marcel F. Jonkman, Leena Bruckner-Tuderman, Cristina Has

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Figure 3

Identification of the reversion mechanism.

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Identification of the reversion mechanism. LDM was used to collect epide...
LDM was used to collect epidermal keratinocytes from areas with altered or normal DEJ morphology. (A) Partial sequence of FERMT1 exon 4 in lymphocytes of P1 showed the duplicating insertion in adenine repeats c.456dupA (A7). The control had the adenine repeat sequence A6. (B) In affected skin sample P1-1, the mutation was found in a homozygous state. Analysis of DNA from microdissected areas (insets) of P1-3 from unaffected skin revealed the mutation in a heterozygous state (A6/7) in the majority of the experiments, but the wild-type sequence (A6) was also found. The sequence in the vicinity of the revertant mutation is shown below; bold denotes the GA6-A6G motif, underline denotes a DNA-polymerase β frameshift hotspot; red denotes the mutation. (C) Partial sequence of FERMT1 exon 5 in lymphocytes of P2 and a control showing the duplicating insertion in a cytosine tract (C8). (D) The homozygous duplication c.676dupC was disclosed in the affected skin P2-1, whereas analysis of DNA from microdissected areas (insets) in unaffected skin P2-2 disclosed the mutation in a heterozygous state (C7/8), or the normal sequence (C7). The sequence in the vicinity of the revertant mutation is shown below; bold denotes the AC6-C6A motif, underline denotes the vertebrate topoisomerase II consensus cleavage site; red denotes the mutation. Scale bars: 50 μm.