What is the NF1 gene?

What is the NF1 Gene?

The NF1 gene is a tumor suppressor gene located on chromosome 17q11.2 that encodes neurofibromin, a protein functioning primarily as a GTPase-activating protein (GAP) that negatively regulates RAS signaling by converting active GTP-bound RAS to its inactive GDP-bound form. 1

Genetic Structure and Location

• The NF1 gene spans approximately 350 kilobases and contains 60 exons on chromosome 17q11.2. 1
• The gene product, neurofibromin, is a large protein consisting of 2,818 amino acids. 1
• Neurofibromin contains a 300-amino acid GAP-related domain (GRD) that is critical for its tumor suppressor function. 1

Molecular Function and Mechanism

• Neurofibromin acts as a negative regulator of the RAS-MAPK signaling pathway by accelerating the conversion of active GTP-bound RAS to its inactive GDP-bound form. 1, 2
• Loss of functional neurofibromin leads to elevated RAS activity, which drives uncontrolled cell growth and proliferation. 1
• The protein is expressed widely across multiple tissues, particularly in cutaneous and nervous systems, explaining the diverse clinical manifestations when mutations occur. 3

Downstream Signaling Pathways

When neurofibromin is absent or dysfunctional due to NF1 mutations, three major RAS effector pathways become dysregulated:

• The MEK-ERK pathway becomes upregulated, promoting cell proliferation and survival. 1
• The PI3K-AKT-mTOR pathway shows increased activity, driving cell growth and tumor development. 1
• The adenylyl cyclase-mediated cAMP signaling pathway becomes altered, contributing to tumor pathogenesis. 1

Clinical Significance

• Germline mutations in the NF1 gene cause neurofibromatosis type 1 (NF1), an autosomal dominant disorder affecting approximately 1 in 2,000-3,000 individuals. 2, 4
• Tumor development in NF1 requires biallelic inactivation—both the inherited mutant allele and somatic loss of the remaining normal allele (following Knudson's two-hit hypothesis). 1, 5
• NF1-associated tumors exhibit elevated RAS activity due to the absence of neurofibromin's negative regulatory function. 1

Tumor Development Mechanism

• In plexiform neurofibromas, neoplastic Schwann cells lack NF1 gene expression and demonstrate elevated levels of activated RAS. 1
• Activated RAS initiates a cascade of signaling events including Raf and MAPK activation that lead to increased cell proliferation. 1
• The tumor microenvironment contributes to pathogenesis, with Schwann cells secreting kit ligand that recruits mast cells and promotes abnormal growth. 1

Developmental Window for Tumorigenesis

• For optic pathway gliomas specifically, somatic NF1 inactivation must occur in susceptible cell types during a restricted developmental window (prior to postnatal day 1 in mouse models) for tumors to form. 1
• This developmental requirement explains why NF1-associated optic pathway gliomas are predominantly tumors of young children. 1

Genetic Testing Implications

• Deep sequencing can identify germline NF1 mutations in 100% of cases when adequate coverage is achieved. 5
• Somatic NF1 inactivation can be detected in approximately 74% of plexiform neurofibromas using whole-exome sequencing. 5
• NF1 is the only gene recurrently somatically inactivated across multiple NF1-associated tumors, confirming its primacy as the driver of tumorigenesis. 5