Neurofibromin Summary

Neurofibromin (NF1) is a large cytoplasmic protein that regulates Ras signaling by stimulating the GTPase activity of the Ras protein, thereby modulating its activation state (UniProt: P21359). The protein comprises 2,839 amino acids and serves as a negative regulator of the Ras pathway, a critical signaling cascade controlling cell proliferation and differentiation.

Loss-of-function mutations in NF1 cause neurofibromatosis type 1 (NF1), characterized by café-au-lait skin spots, iris Lisch nodules, and tumors of peripheral nerves with increased cancer susceptibility (UniProt: P21359). NF1 mutations also underlie related neurodevelopmental conditions including Watson syndrome—presenting with pulmonary stenosis, pigmentation abnormalities, and intellectual disability—and Neurofibromatosis-Noonan syndrome, which combines features of both NF1 and Noonan syndrome with motor delay and cardiac anomalies. Additional disease associations include juvenile myelomonocytic leukemia, familial spinal neurofibromatosis, and colorectal cancer predisposition.

NF1 is classified as a syndromic autism-spectrum risk gene by SFARI (SFARI Cat S), indicating that autism or developmental delay features appear as part of multi-system NF1-related presentations rather than as a primary phenotype of isolated mutations.