Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Neurofibromatosis type I (NF1) is primarily caused by mutations in the NF1 gene.
• Most NF1 mutations lead to reduced neurofibromin protein via truncation or deletion.
• The impact of missense variants on NF1 pathogenesis is less understood.

Purpose of the Study:

• Investigate the mechanism of loss-of-function missense variants in the NF1 gene.
• Understand how specific NF1 variants contribute to disease severity.
• Establish genotype-phenotype correlations for NF1 missense variants.

Main Methods:

• Analysis of patient-derived NF1 variants in codons 844-848.
• Assessment of neurofibromin protein stability and dimerization.
• Utilizing cryogenic electron microscopy (cryo-EM) structure of neurofibromin.
• Prediction and validation of additional patient variants based on structural insights.

Main Results:

• NF1 variants in codons 844-848 lead to neurofibromin protein instability.
• These variants exhibit a dominant-negative effect, destabilizing wild-type neurofibromin through dimerization.
• Structural analysis enabled prediction and validation of similar pathogenic mechanisms in other variants.

Conclusions:

• Missense variants can drive NF1 disease through protein instability and dominant-negative effects.
• Understanding these mechanisms is crucial for predicting NF1 genotype-phenotype correlations.
• Findings have implications for NF1 patient counseling, management, and therapeutic strategies.