RESUMO
Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in the F13A1 gene encoding factor XIII subunit A (FXIII-A), a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has an allele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, the treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation, and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and α4ß1 integrins, more prominently for Lys679Met FXIII-A than the wild type. In addition, both the α4ß1 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine-Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may lead to a conformational change in the FXIII-A protein that enhances α4-integrin binding and provides insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.
Assuntos
Fator XIII/genética , Fibrina/metabolismo , Histiocitoma Fibroso Benigno/genética , Padrões de Herança , Pele/patologia , Domínio Catalítico/genética , Proliferação de Células/genética , Colágeno Tipo I/biossíntese , Análise Mutacional de DNA , Fator XIII/metabolismo , Feminino , Fibroblastos , Células HEK293 , Histiocitoma Fibroso Benigno/patologia , Humanos , Integrina alfa4/metabolismo , Masculino , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Linhagem , Conformação Proteica em alfa-Hélice/genética , Conformação Proteica em Folha beta/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Pele/citologia , Relação Estrutura-Atividade , Sequenciamento do ExomaRESUMO
Distichiasis is defined as a double row of eyelashes. Inherited forms of distichiasis have been associated with early and late-onset congenital lymphedema. We report on a child with distichiasis and congenital lymphedema in which it is unknown whether the cause of lymphedema was due to a spontaneous mutation or acquired secondary to an intrauterine infection. Acquired forms of distichiasis are reviewed.
Assuntos
Anormalidades Múltiplas , Pestanas/anormalidades , Linfedema/congênito , Pré-Escolar , Humanos , Linfedema/complicações , MasculinoRESUMO
Benign fibrous histiocytomas of the skin, or dermatofibromas, are common fibrohistiocytic tumors that affect women more commonly than men. Proposed causes range from a reactive process to a neoplastic growth. We report on a family affected with numerous dermatofibromas, suggesting that there also may be a genetic cause to this common tumor.
