RESUMO
Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.
Assuntos
Aneurisma/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Artéria Retiniana/patologia , Adolescente , Adulto , Aneurisma/patologia , Sequência de Bases , Criança , Pré-Escolar , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Família , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Splicing de RNA/genética , Artéria Retiniana/enzimologia , Regulação para Cima/genética , Adulto JovemRESUMO
Autosomal recessive ataxias are heterogeneous group of disorders characterized by cerebellar atrophy and peripheral sensorimotor neuropathy. Molecular characterization of this group of disorders identified a number of genes contributing to these overlapping phenotypes. Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive form of ataxia caused by mutations in the SETX gene. We report on a consanguineous family with autosomal recessive inheritance and clinical characteristics of AOA2, and no mutations in the SETX gene. We mapped the AOA locus in this family to chromosome 17p12-p13. Sequencing of all genes in the refined region identified a homozygous missense mutation in PIK3R5 that was absent in 477 normal controls. Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis.
Assuntos
Apraxias/genética , Ataxia Telangiectasia/genética , Ataxia/genética , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Hipoalbuminemia/genética , Mutação de Sentido Incorreto , Fosfatidilinositol 3-Quinases/genética , Adolescente , Adulto , Animais , Apraxias/diagnóstico , Ataxia/diagnóstico , Ataxia Telangiectasia/diagnóstico , Encéfalo/patologia , Ataxia Cerebelar/congênito , Consanguinidade , DNA Helicases , Feminino , Ordem dos Genes , Ligação Genética , Homozigoto , Humanos , Hipoalbuminemia/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Camundongos , Enzimas Multifuncionais , Linhagem , Fenótipo , RNA Helicases/genética , Relações entre Irmãos , Adulto JovemRESUMO
BACKGROUND: Knobloch syndrome (KS) is a developmental disorder characterised by occipital skull defect, high myopia, and vitreo-retinal degeneration. Although genetic heterogeneity has been suspected, COL18A1 is the only known KS disease gene to date. OBJECTIVE: To identify a novel genetic cause of KS in a cohort of Saudi KS patients enrolled in this study. METHODS: When COL18A1 mutation was excluded, autozygosity mapping was combined with exome sequencing. RESULTS: In one patient with first cousin parents, COL18A1 was excluded by both linkage and direct sequencing. By filtering variants generated on exome sequencing using runs of autozygosity in this simplex case, the study identified ADAMTS18 as the only gene carrying a homozygous protein altering mutation. It was also shown that Adamts18 is expressed in the lens and retina in the developing murine eye. CONCLUSION: The power of combining exome and autozygome analysis in the study of genetics of autosomal recessive disorders, even in simplex cases, has been demonstrated.
Assuntos
Proteínas ADAM/genética , Encefalocele/genética , Mutação , Descolamento Retiniano/congênito , Proteínas ADAM/metabolismo , Proteínas ADAMTS , Animais , Sequência de Bases , Consanguinidade , Embrião de Mamíferos/metabolismo , Encefalocele/metabolismo , Encefalocele/patologia , Exoma , Feminino , Heterogeneidade Genética , Humanos , Cristalino/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Fenótipo , Retina/metabolismo , Degeneração Retiniana , Descolamento Retiniano/genética , Descolamento Retiniano/metabolismo , Descolamento Retiniano/patologiaRESUMO
BACKGROUND: Osteodex is a novel bi-functional macromolecular polybisphosphonate developed for treatment of bone metastases in prostate and breast cancer. High efficacy of osteodex has been demonstrated both in vitro and in vivo. The present study investigates whether osteodex is also efficacious on soft tissue tumor lesions. MATERIALS AND METHODS: Twelve female nude mice were injected with MDA-MB-231 cells orthotopically. Osteodex was administered i.v. at 2.5 mg/kg, once per week for five weeks. Tumor volumes were measured during the treatment period, the animals were sacrificed, and samples collected for proteomic analysis. RESULTS: The non-treated mice developed multiple tumors greater than 4 cm with pronounced ulceration, while the treated mice had tumors smaller than 1 cm, without ulceration. While general condition of treated mice was good, non-treated animals were in poor condition. Sixteen out of 300 identified proteins were differentially expressed, with statistically significant expression changes of more than two-fold differences between treated and non-treated groups. These proteins were identified using non-gel based nano-liquid chromatography coupled with a Synapt G2 instrument. CONCLUSION: We conclude that osteodex showed significant treatment efficacy on soft tissue tumor implants. The study provides a global view of changes in protein expression profiles following osteodex treatment. Some functions of the identified proteins might be used to explain the specific treatment efficacy of osteodex.