The majority of pathogenic mutations in the neurofibromatosis type I ( NF1 ) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype–phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.

The Sudden Oak Death or SOD Blitzes consist of yearly surveys led by citizen scientists designed to map the distribution of Phytopthora ramorum, causing the forest disease called SOD, across Northern California. During the 2017 Santa Cruz County SOD Blitz, six rare or endangered Arctostaphylos (manzanita) species were found to be possibly symptomatic for the first time. Symptoms included branch cankers and associated canopy mortality, and affected multiple individuals per species. Isolates of Phytophthora ramorum were obtained from each of the six species and through a 30-day long inoculation experiment on live plants, Koch’s postulates were completed for each one of them, conclusively determining that they all are hosts of this pathogen. Two additional manzanita species were later found to be apparently symptomatic in Marin County. Inoculations on detached branches using an isolate of P. ramorum obtained from one of the six rare species from Santa Cruz County were successful, suggesting these two species may also be hosts of P. ramorum. Detached leaves of all eight species were also successfully inoculated at U.C. Berkeley in the Fall of 2018 and then again in the Spring of 2019. In these cases, the same isolate was used for all inoculations, in order to obtain information on the comparative susceptibility of the eight species in question. Both branch and leaf inoculations identified significant interspecific differences in susceptibility. The production of sporangia was low on all species, but it was not zero, suggesting that sporulation may cause within-plant and limited across-plant contagion, especially in rainy years.