Human Genetics and Genetic Diseases

Biography

Biography: Meena Upadhyaya

Abstract

Neurofibromatosis type 1 (NF1) is a common autosomal dominantly inherited tumor predisposition syndrome affecting 1/3000-4000 individuals worldwide. Neurofibromin, the protein encoded by NF1 gene down-regulates Ras. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation and senescence, all of which are critical to normal development. In NF1 patients, benign plexiform neurofibromas can transform into aggressive malignant tumors called Malignant Peripheral Nerve Sheath Tumors (MPNSTs), currently, there are no effective treatments for MPNSTs. The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/MAPK pathway. These disorders include neurofibromatosis type 1, Legius syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines (LEOPARD), capillary arteriovenous malformation syndrome, Costello syndrome cardiofaciocutaneous syndrome and SYNGAP1 autism. Because of the common underlying Ras/MAPK pathway dysregulation, they have overlapping phenotypic features, including cancer, facial dysmorphia, neurocognitive impairment, pain and cardiovascular, musculoskeletal, gastrointestinal and cutaneous abnormalities. NF1 was the first Rasopathy syndrome reported in the RAS pathway. Several ongoing clinical trials exist for RASopathies including NF1 and effective treatments for certain clinical features are on horizon. NF1 also has great importance and significance in a number of sporadic cancers and functions as a central tumor suppressor gene in these cancers. With the recent advances in sequencing technologies, high-throughput drug discovery platforms, increasing availability of more sophisticated animal models and application of the state-of-art tumor imaging techniques, diagnosis and treatment of patients with RASopathies is improving.