The Molecular Biology of Neurofibromatosis Type 1: Neurofibromatosis Type 1

ISBN-13: 9781615046447 / Angielski / Miękka / 2014 / 79 str.

Meena Upadhyaya

Opis

Neurofibromatosis type 1 (NF1) is a common autosomaldominantly inherited tumour predisposition syndrome affecting 1/3000-4000 individuals worldwide (Huson et al., 1988; Lammert et al., 2005). This inherited disorder results from the mutational inactivation of the NF1 gene on human chromosome 17. NF1 manifests a variety of characteristic clinical features, including hyperpigmentary abnormalities of the skin (caf -au-lait macules and inguinal/axillary freckling), iris hamartomas (Lisch nodules) and the growth of benign peripheral nerve sheath tumours (neurofibromas) in the skin. These neurofibromas display several different subtypes and are associated with a variety of clinical complications. Cutaneous neurofibromas are discrete small dermal tumours observed in almost all adult NF1 patients. The usually much larger plexiform neurofibromas (PNFs), a more diffuse tumour type, are present in 30-50% of NF1 patients, and, importantly, some 10- 15% of these benign tumours subsequently become transformed into aggressive malignant peripheral nerve sheath tumours (MPNSTs), the main cause of morbidity in NF1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominantly inherited, tumour predisposition syndrome affecting 1/3,000-4,000 individuals worldwide. This inherited disorder results from the mutational inactivation of the NF1 gene on human chromosome 17. The NF1 gene contains 61 exons that give rise to 12kb mRNA encoding neurofibromin. The 327kDa (2,818 amino acid) neurofibromin protein is expressed in most tissues and has a number of alternative isoforms. Neurofibromin is a tumour suppressor protein and down-regulates cellular Ras. Increased active Ras-GTP levels also stimulate the important PI3K/AKT/mTOR signalling pathway that protects cells from apoptosis.The major clinical featues of NF1 include multiple café-au-lait macules, skinfold freckles, iris Lisch nodules, and neurofibromas. The diagnostic criteria for clinical diagnosis have been well established. However, there are a small number of cases in which the diagnosis is not certain. The germline mutation rate for the NF1 gene is 10-fold higher than that observed for most other inherited diseases. Using a combination of different techniques, almost 95% of germline mutations can be detected. To date, only two firm genotype phenotype correlations have been reported. NF1 phenotype exhibits large variations within a family, evidence for modifying loci regulating the expression of an NF1 gene is beginning to emerge. We also are gaining knowledge on the molecular mechanisms associated with the development of different types of tumours. It is encouraging that the results of recent laboratory and clinical research are finally being translated into clinical trials. With the availability of high-throughput technologies, sophisticated animal models, and multi-centre clinical trials, the future for NF1 sufferers is looking optimistic.This book aims to provide an overview of the genetic and clinical aspects of NF1 and its role in both NF1-associated and sporadic tumour development. It emphasizes the recent developments in this field and some of the promising on-going clinical trials.

Spis treści

• Abbreviations
• Introduction to NF1
• NF1-Associated Tumours
• Animal Models, Preclinican and Clinical Trials
• Summary and Conclusion
• References
• Titles of Related Interest
• Series of Related Interest