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Analysis of patient-specific NF1 variants leads to functional insights for Ras signaling that can impact personalized medicine

We have created a panel of twenty-nine NF1 variant cDNAs representing
benign missense (MS) variants, pathogenic MS variants, many with
clinically relevant phenotypes, in-frame deletions, splice variants, and
nonsense (NS) variants. We have determined the functional consequences
of the variants, assessing their ability to produce mature neurofibromin
and restore Ras signaling activity in NF1 null (-/-) cells. cDNAs
demonstrate variant-specific differences in neurofibromin protein
levels, suggesting that some variants lead to protein instability or
enhanced degradation. When expressed at high levels, some variant
proteins are still able to repress Ras activity, indicating that the NF1
phenotype may be due to protein instability. In contrast, other variant
proteins are incapable of repressing Ras activity, indicating that some
do not functionally engage Ras and stimulate GTP-ase activity. We
observed that stability and Ras activity can be mutually exclusive.
These assays allow us to categorize variants by functional effects, may
help to classify variants of unknown significance, and may have future
implications for more directed therapeutics.