Pathogenesis of multiple lentigines in LEOPARD syndrome with PTPN11 gene mutation.
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.
Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. smotegi@gunma-u.ac.jp.
Sei-Ichiro
S
Motegi
Yoko
Y
Yokoyama
Sachiko
S
Ogino
Kazuya
K
Yamada
Akihiko
A
Uchiyama
Buddhini
B
Perera
Yuko
Y
Takeuchi
Hiroshi
H
Ohnishi
Osamu
O
Ishikawa
D000293:Adolescent; D019332:Endothelin-1 / Q000032:analysis; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000648:ultrastructure*; D044542:LEOPARD Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000378:metabolism / Q000648:ultrastructure*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D020460:Melanosomes / Q000648:ultrastructure; D009154:Mutation; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000032:analysis; D015398:Signal Transduction; D012867:Skin / Q000737:chemistry / Q000648:ultrastructure; D058570:TOR Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism; D014407:Tumor Cells, Cultured; D055815:Young Adult
D019332:Endothelin-1; D008543:Melanins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11