Neurofibromatosis type 1: Its association with the Ras/MAPK pathway syndromes

Abstract

Neurofibromatosis type 1 (NF1) is a common (affects ∼1 in 4000 individuals worldwide) autosomal dominant neurocutaneous syndrome, resulting from functional inactivation of the NF1 gene. The main clinical features include dermal pigmentary changes (cafe-au-lait spots and skin fold freckling), development of benign peripheral nerve sheath-derived tumors (neurofibromas) and hamartomas of the iris (Lisch nodules). Benign tumor development, involving peripheral nerves and the central nervous system, are hallmark features of NF1. Associated clinical manifestations can include abnormalities of the cardiovascular, gastrointestinal, renal and endocrine systems, orthopedic problems, macrocephaly, small stature, facial and body dysmorphism, learning disabilities, and an increased malignancy risk. Neurofibromin, the NF1 gene product, is a mammalian Ras GTPase-activating protein expressed in most tissues, with functional inactivation leading to increased cellular Ras signaling, resulting in cell growth, proliferation and tumorigenesis, underlining its role as a tumor suppressor gene. At least 1050 different disease-causing NF1 mutations are known, although correlating different mutations with specific clinical features has proved largely unsuccessful, with only two such associations identified. One relating to severely affected NF1 patients with large genomic deletions that involve the entire NF1 gene, and the other, relating to some mildly affected NF1 patients without any cutaneous neurofibromas, who have the same specific 3bp NF1 gene deletion. Several animal NF1 models have been developed that have allowed analysis of NF1 gene inactivation and proved crucial in unravelling the complexity of the Ras signaling pathway and its role in regulating cell proliferation, differentiation, motility, apoptosis and tumorigenesis. Such models have also better defined the probable causes of NF1-related learning difficulties, skeletal abnormalities, and also identified neurofibromin as a cellular cyclic AMP regulator. It is now recognized that mutations of a number of the genes in the complex RAS-MAPK signaling pathway are associated with several neuro-cardio-facial-cutaneous syndromes, a group of pheno- and genotypically similar developmental disorders, that includes NF1. The recent identification of SPRED1 gene mutations in individuals with mild NF1-like features extends this disease association with spred proteins known to be directly involved in RAS-MAPK pathway. No effective treatment for NF1 is currently available, with many proposed therapies, often aimed at preventing tumor growth, showing little success, although a statin-based treatment has proved useful in treating a mouse NF1 model with learning disability and tibial dysplasia. Several proposed therapies targeting mast cell function, different Ras signaling pathway components, as well as growth factor receptors, may hopefully prove more successful.