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Neurofibromatosis 1 : Molecular Genetics

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Neurofibromatosis 1 is caused by genetic defects (deletions, insertions, substitutions, stop mutations, splicing mutations) in the tumor suppressor gene NF1 on chromosome 17q11.2. NF1 is a very large gene that codes for Neurofibromin - a 2800 amino acid protein that is expressed in brain and peripheral nerves. It is a RAS GTPase-activating protein that negatively regulates (inactivates) RAS proteins. Loss of NF1 function causes increased RAS activity which activates downstream signaling pathways leading to cellular proliferation and tumor formation.

RASopathies: NF1 belongs to a group of related inherited cancer predisposition syndromes caused by germline mutations in genes of RAS/Mitogen-Activated Protein Kinase (MAPK) pathway. They are collectively known as RASopathies. In addition to NF1, it includes Noonan Syndrome, Noonan Syndrome with Multiple Lentigines, Costello Syndrome, Legius Syndrome, Autoimmune Lymphoproliferative Syndrome, Hereditary Gingival Fibromatosis Type 1, and others.

The RAS/MAPK pathway is a signal transduction pathway that plays a critical role in normal mammalian development by regulating the cell cycle and cellular growth, differentiation, and senescence. Its dysregulation leads to serious developmental disroders, including craniofacial dysmorphology; cardiac malformations; cutaneous, musculoskeletal, and ocular abnormalities; neurocognitive impairment; hypotonia; and an increased cancer risk.

Reference: Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14:355-369.

This image showing ribbon structure of Neurofibromin was originally uploaded by ProteinBoxBot at English Wikipedia - Transferred from en.wikipedia to Commons., Public Domain, Link

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