RESUMO
There are no reports on the relationship between familial medullary thyroid carcinoma (FMTC) associated with cutaneous amyloidosis (CA) and RET or OSMR/IL31RA gene mutations. In this study, we investigated a Chinese family with FMTC/CA and found a recurrent RET c.2671T>G (p.S891A) mutation in six of 17 family members. Three of the six p.S891A mutation carriers presented with medullary thyroid carcinoma (MTC). Of them, three (two with and one without MTC) were diagnosed as having combined lichen/macular biphasic CA. We also identified a novel RET variant, c.1573C>T (p.R525W) in five members. Of them, three carriers had no evidence of thyroid/skin or basal serum/stimulated calcitonin abnormalities. In vitro cell proliferation assay indicated that oncogenic activity of RET p.S891A was slightly enhanced by p.R525W, whereas p.R525W alone had no effect on cell proliferation. Meanwhile, we identified a novel OSMR variant, c.1538G>A (p.G513D) in seven members. We noticed that three OSMR p.G513D carriers presenting with CA also had the RET p.S891A mutation. Our investigation indicated that the RET p.S891A mutation combined with OSMR p.G513D may underlie a novel phenotype manifesting as FMTC and CA.
Assuntos
Amiloidose Familiar/genética , Carcinoma Medular/congênito , Neoplasia Endócrina Múltipla Tipo 2a/genética , Mutação , Subunidade beta de Receptor de Oncostatina M/genética , Proteínas Proto-Oncogênicas c-ret/genética , Dermatopatias Genéticas/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Idoso , Amiloidose Familiar/complicações , Amiloidose Familiar/metabolismo , Calcitonina/metabolismo , Carcinoma Medular/genética , Carcinoma Medular/metabolismo , Proliferação de Células , Criança , China , Análise Mutacional de DNA , Saúde da Família , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Estudos de Associação Genética , Variação Genética , Vetores Genéticos , Mutação em Linhagem Germinativa , Células HEK293 , Heterozigoto , Humanos , Masculino , Neoplasia Endócrina Múltipla Tipo 2a/metabolismo , Fenótipo , Dermatopatias Genéticas/complicações , Dermatopatias Genéticas/metabolismo , Neoplasias da Glândula Tireoide/metabolismoRESUMO
To investigate the antitumor mechanism of artemisninin, a flexible docking analysis was used to score all kinds of functions of 11 Qinghaosu derivatives and transferrin with different resolutions. The distances of Asp-63, Tyr-188, His-249, Arg-124 and Lys-296 with Qinghaosu were less than 0.5 nm, separately. Meanwhile, the higher is the activity of Qinghaosu derivatives the higher is the score. Our model explains that Fe2+ is more feasible to react with Qinghaosu, and not involved in other metabolism in presence of transferrin. Docking results unveil that Iron(II)-transferrin increased the cytotoxicity of Qinghaosu derivatives and provide a rational basis for further design and synthesis of novel Qinghaosu derivatives.