RT Journal Article
SR Electronic
T1 Somatic recombination underlies frequent revertant mosaicism in loricrin keratoderma
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800284
DO 10.26508/lsa.201800284
VO 2
IS 1
A1 Shotaro Suzuki
A1 Toshifumi Nomura
A1 Toshinari Miyauchi
A1 Masae Takeda
A1 Yasuyuki Fujita
A1 Wataru Nishie
A1 Masashi Akiyama
A1 Akemi Ishida-Yamamoto
A1 Hiroshi Shimizu
YR 2019
UL https://www.life-science-alliance.org/content/2/1/e201800284.abstract
AB Revertant mosaicism is a phenomenon in which pathogenic mutations are rescued by somatic events, representing a form of natural gene therapy. Here, we report on the first evidence for revertant mosaicism in loricrin keratoderma (LK), an autosomal dominant form of ichthyosis caused by mutations in LOR on 1q21.3. We identified two unrelated LK families exhibiting dozens of previously unreported white spots, which increased in both number and size with age. Biopsies of these spots revealed that they had normal histology and that causal LOR mutations were lost. Notably, dense single nucleotide polymorphism mapping identified independent copy-neutral loss-of-heterozygosity events on chromosome 1q extending from regions centromeric to LOR to the telomere in all investigated spots, suggesting that somatic recombination represents a common reversion mechanism in LK. Furthermore, we demonstrated that reversion of LOR mutations confers a growth advantage to cells in vitro, but the clinically limited size of revertant spots suggests the existence of mechanisms constraining revertant clone expansion. Nevertheless, the identification of revertant mosaicism in LK might pave the way for revertant therapy for this intractable disease.