JOURNAL ARTICLE

Pathogenesis of multiple lentigines in LEOPARD syndrome with PTPN11 gene mutation

Sei-Ichiro Motegi, Yoko Yokoyama, Sachiko Ogino, Kazuya Yamada, Akihiko Uchiyama, Buddhini Perera, Yuko Takeuchi, Hiroshi Ohnishi, Osamu Ishikawa
Acta Dermato-venereologica 2015, 95 (8): 978-84
25917897
LEOPARD syndrome (LS) is an autosomal dominant condition with multiple anomalies, including multiple lentigines. LS is caused by mutations in PTPN11, encoding the protein tyrosine phosphatase, SHP-2. We report here 2 unrelated Japanese cases of LS with different PTPN11 mutations (p.Y279C and p.T468P). To elucidate the pathogenesis of multiple lentigines in LS, ultrastructural and immunohistochemical analyses of lentigines and non-lesional skin were performed. Numerous mature giant melanosomes in melanocytes and keratinocytes were observed in lentigines. In addition, the levels of expression of endothelin-1 (ET-1), phosphorylated Akt, mTOR and STAT3 in the epidermis in lentigines were significantly elevated compared with non-lesional skin. In in vitro assays, melanin synthesis in human melanoma cells expressing SHP-2 with LS-associated mutations was higher than in cells expressing normal SHP-2, suggesting that LS-associated SHP-2 mutations might enhance melanin synthesis in melanocytes, and that the activation of Akt/mTOR signalling may contribute to this process.

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