Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype
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ABSTRACT: Of the RAF family of protein kinases, BRAF is the only member to be frequently activated by mutation in cancer. A single amino acid substitution (V600E) accounts for the vast majority and results in constitutive activation of BRAF kinase function. Its expression is required to maintain the proliferative and oncogenic characteristics of BRAF(E600)-expressing human tumour cells. Although BRAF(E600) acts as an oncogene in the context of additional genetic lesions, in primary cells it appears to be associated rather with transient stimulation of proliferation. Eventually, BRAF(E600) signalling triggers cell cycle arrest with the hallmarks of cellular senescence, as is illustrated by several recent studies in cultured cells, animal models and benign human lesions. In this review, we will discuss recent advances in our understanding of the role of BRAF(E600) in benign and malignant human tumours and the implications for therapeutic intervention.Oncogene 03/2008; 27(7):877-95. DOI:10.1038/sj.onc.1210704 · 8.56 Impact Factor
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ABSTRACT: Costello syndrome is an autosomal dominant disorder comprising growth deficiency, mental retardation, curly hair, coarse facial features, nasal papillomata, low-set ears with large lobes, cardiac anomalies, redundant skin in palms and soles with prominent creases, dark skin, and propensity to certain solid tumors. HRAS mutations have been implicated in approximately 85% of the affected cases. The clinical overlap among Costello, Noonan, and cardiofaciocutaneous syndromes is now better understood given their common molecular background, such that all these syndromes constitute a class of disorders caused by deregulated RAS-MAPK signaling. We report on a novel KRAS gene mutation in a patient presenting the clinical features typical of Costello syndrome and the additional findings seen in Noonan syndrome. This description emphasizes that a subset of patients with Costello syndrome could harbor mutations in other genes involved in the RAS-MAPK signaling.Journal of Human Genetics 02/2007; 52(6):521-6. DOI:10.1007/s10038-007-0146-1 · 2.53 Impact Factor
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ABSTRACT: Research based on Landsat image interpretation, GIS-topographic mapping,historical records, and ground truthing indicates that the evolution of the muddy coast and the expansion of the Pearl River delta have been strongly affected by human activities in historical times. In recent decades the region has experienced severe man-induced siltation coupled with rapid but premature reclamation of muddy tidal flats in the wake of economic development and population expansion.At present, there is practically no natural coastal landscape left, the shoreline beingcharacterized by man-made dikes throughout. In addition, most of the delta plain is poorly protected, being situated below local high-tide and storm-surge levels. The delta region is thus exposed to natural disasters such as typhoon-driven storm surges and ground subsidence caused by local sediment compaction and regional tectonics. These effects are compounded by the threat of accelerated relative sea-level rise which has been estimated to reach 0.5 m within the next 50 years. Without massive protection works this would lead to the inundation of 96.5% of the delta region, and would include the destruction of even entire cities such as Guangzhou.We contend that the effects of human interventions in the Pearl River delta region have reached the same significance as those associated with geological processes. This important aspect has to be taken into account when studying the recent evolution of the delta, especially when seeking sustainable solutions for the economic development of the region.