1. Pathogenesis of multiple lentigines in LEOPARD syndrome with PTPN11 gene mutation
- Author
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Sei-ichiro Motegi, Hiroshi Ohnishi, Akihiko Uchiyama, Kazuya Yamada, Buddhini Perera, Yoko Yokoyama, Sachiko Ogino, Osamu Ishikawa, and Yuko Takeuchi
- Subjects
Keratinocytes ,STAT3 Transcription Factor ,Pathology ,medicine.medical_specialty ,Adolescent ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Dermatology ,Protein tyrosine phosphatase ,Biology ,medicine.disease_cause ,LEOPARD Syndrome ,Young Adult ,medicine ,Tumor Cells, Cultured ,Humans ,Phosphorylation ,Protein kinase B ,Melanoma ,PI3K/AKT/mTOR pathway ,Melanosome ,Skin ,Melanins ,Mutation ,Melanosomes ,Endothelin-1 ,TOR Serine-Threonine Kinases ,PTPN11 Gene Mutation ,General Medicine ,PTPN11 ,Cancer research ,Melanocytes ,Female ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
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.
- Published
- 2015