Revertant Mosaicism in Genodermatoses: Natural Gene Therapy Right before Your Eyes

Abstract

Revertant mosaicism (RM) is the intriguing phenomenon in which nature itself has successfully done what medical science is so eagerly trying to achieve: correcting the effect of disease-causing germline variants and thereby reversing the disease phenotype back to normal. RM was molecularly confirmed for the first time in a genodermatosis in 1997, the genetic skin condition junctional epidermolysis bullosa (EB). At that time, RM was considered an extraordinary phenomenon. However, several important discoveries have changed this conception in the past few decades. First, RM has now been identified in all major subtypes of EB. Second, RM has also been identified in many other genodermatoses. Third, a theoretical mathematical exercise concluded that reverse mutations should be expected in all patients with a recessive subtype of EB or any other genodermatosis. This has shifted the paradigm from RM being an extraordinary phenomenon to it being something that every physician working in the field of genodermatoses should be looking for in every patient. It has also raised hope for new treatment options in patients with genodermatoses. In this review, we summarize the current knowledge on RM and discuss the perspectives of RM for the future treatment of patients with genodermatoses.

Effects of TP63 mutations on keratinocyte adhesion and migration

“…Finally, the focal nature of adhesion protein downregulation in AEC patient skin suggests the existence of mechanisms that restore or maintain hemidesmosomal and focal adhesion proteins in the presence of TP63 mutations. There is currently no evidence for the existence of a genetic mechanism, such as revertant mosaicism, 37 to explain this phenomenon. Regardless of the genetic or epigenetic mechanism, the ability to restore adhesion is consistent with the observation that AEC skin erosions heal over time and are generally small or absent in adult patients.…”

Emerging Gene Therapeutics for Epidermolysis Bullosa under Development

“…At first considered a rare phenomenon, revertant mosaicism was, in a later study, shown to be present in the majority of patients with COL17A1-associated JEB; it has subsequently been detected in all major EB subtypes [14,15]. Although a proof of principle transplantation of autologous revertant keratinocytes was successfully performed on a laminin-deficient patient, several obstacles, including the isolation of revertant stem cells, need to be addressed before it can provide a safe and efficient therapeutic treatment option [15,16].…”

Inherited Reticulate Pigmentary Disorders

“…Specifically, revertant mosaicism has been reported in epidermolysis bullosa simplex due to KRT14 mutations [ 91 , 92 , 93 ]. It might be hypothesized that revertant mosaicism exists among clinical manifestations of the NFJS [ 94 ].…”