RESUMO
Börjeson-Forssman-Lehmann syndrome (BFLS; OMIM 301900) is characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure and large but not deformed ears. Previously, the gene associated with BFLS was localized to 17 Mb in Xq26-q27 (refs 2-4). We have reduced this interval to roughly 9 Mb containing more than 62 genes. Among these, a novel, widely expressed zinc-finger (plant homeodomain (PHD)-like finger) gene (PHF6) had eight different missense and truncation mutations in seven familial and two sporadic cases of BFLS. Transient transfection studies with PHF6 tagged with green fluorescent protein (GFP) showed diffuse nuclear staining with prominent nucleolar accumulation. Such localization, and the presence of two PHD-like zinc fingers, is suggestive of a role for PHF6 in transcription.
Assuntos
Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Motivos de Aminoácidos , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Nucléolo Celular/metabolismo , Núcleo Celular/metabolismo , Embrião de Mamíferos/metabolismo , Feminino , Proteínas de Fluorescência Verde , Células HeLa , Heterozigoto , Humanos , Proteínas Luminescentes/metabolismo , Masculino , Camundongos , Repetições de Microssatélites , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Mapeamento Físico do Cromossomo , Alinhamento de Sequência , Síndrome , Transfecção , Cromossomo X , Dedos de ZincoRESUMO
CFC syndrome is a genetically heterogenous condition. Missense mutations have been identified in BRAF, KRAS, MEK1 and MEK2. We have reported here a KRAS mutation in a baby girl with an early clinical diagnosis of CFC syndrome associated with a large ulcerating hemangioma. Although ectodermal abnormalities have been described in all individuals with this condition, features such as ichthyosis and hemangioma have been previously found only in those patients carrying a mutation in BRAF, and not in KRAS. The findings we have described contrast with these observations. The relatively high frequency of hemangiomas in CFC syndrome suggests that defects in the expression of the MAPK pathway may alter endothelial cell proliferation. Increased understanding of how the molecular pathways with which defects in CFC syndrome predispose affected individuals to hemangiomas might offer insights into the pathogenesis of this common childhood tumour in the general population.