Genetic Cause of Neurofibromatosis
Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 tumor suppressor gene on chromosome 17, which encodes neurofibromin—a negative regulator of the RAS-MAPK pathway—while neurofibromatosis type 2 (NF2) is caused by mutations in the NF2 gene on chromosome 22, which encodes merlin (schwannomin). 1
Neurofibromatosis Type 1 (NF1) Genetic Basis
Primary Genetic Defect
- The NF1 gene mutation results in loss of functional neurofibromin protein, which normally inhibits RAS signaling to control cell growth and survival. 2
- The NF1 gene is located on chromosome 17 and encodes a large protein of approximately 2,800 amino acids (~220 kDa). 2
- Neurofibromin contains a critical domain (280–300 amino acids) that functions structurally and functionally as a negative RAS regulator. 2
Inheritance Pattern and Mutation Characteristics
- NF1 follows autosomal dominant inheritance with complete penetrance but variable expressivity, meaning offspring have a 50% recurrence risk for each pregnancy. 1, 3
- Approximately 50% of NF1 cases result from de novo (spontaneous) mutations rather than inherited mutations. 3, 4
- Over 1,485 different mutations have been identified in the NF1 gene, with point mutations accounting for approximately 90% of cases. 4
- Most mutations are loss-of-function mutations that result in synthesis of truncated, non-functional neurofibromin protein. 4
- The remaining 5-7% of cases involve single exon deletions or whole NF1 gene deletions (17q11.2 microdeletion syndrome). 4
Molecular Pathogenesis
- Decreased neurofibromin levels lead to increased RAS cascade signaling to downstream effectors, particularly through the RAS/MAPK and Akt/mTOR pathways. 5
- For tumor formation (such as neurofibromas), a "two-hit" mechanism typically occurs: somatic loss of the second NF1 allele (loss of heterozygosity) in progenitor cells (Schwann cells or precursors), combined with haploinsufficiency in supporting cells. 5
- Malignant transformation requires accumulation of additional mutations in genes including INK4A/ARF and P53. 5
Neurofibromatosis Type 2 (NF2) Genetic Basis
Primary Genetic Defect
- The NF2 gene on chromosome 22 encodes merlin (also called schwannomin), a tumor suppressor protein. 1
- NF2 is also inherited in an autosomal dominant pattern with a high rate of new mutations. 6
Key Distinction from NF1
- Although NF1 and NF2 share a common name, they are completely distinct genetic disorders caused by mutations in two different genes on different chromosomes. 6, 7
- NF2 is much rarer than NF1, affecting approximately 1:25,000 persons compared to 1:2,000-3,000 for NF1. 1
Clinical Pitfall
- Somatic mosaicism is well documented in NF1 and may present with variable or few clinical features, making diagnosis challenging in some cases. 3
- When NF1 is suspected but diagnostic criteria are not met, consider alternative diagnoses including Legius syndrome (SPRED1 mutations), other mosaic RASopathies (KRAS), and constitutional mismatch repair deficiency. 3