Phenotype‐based diagnostic criteria were developed for Proteus syndrome in 1999 and updated in 2006. Subsequently, the causative mosaic gene alteration was discovered, the c.49G>A p.E17K variant in AKT1. As well, a number of overlapping overgrowth disorders attributable to mosaic PIK3CA variants have now been characterized, leading to the designation of PIK3CA‐related overgrowth spectrum (PROS). Finally, ongoing work to better characterize Proteus syndrome has led to identification of additional features of that disorder that could be useful in diagnostic criteria. We have taken the opportunity of these discoveries to re‐evaluate the Proteus syndrome diagnostic criteria. Here we propose a new set of diagnostic criteria that establishes a weighted, point‐based system for the phenotypic attributes and then integrates that with the potential molecular test results to result in one of two designations: AKT1‐related Proteus syndrome or AKT1‐related overgrowth spectrum. A patient whose only manifestation is an AKT1 c.49G>A‐positive tumor would receive neither of these designations. Here we review the rational basis of diagnostic criteria and argue that a unitary diagnostic entity is a distinct gene‐phenotype dyad and that this should be the model for all mendelian disorders. The gene‐alone or phenotype‐alone approach is inadequate to rigorously delineate a unitary diagnostic entity.
Proteus syndrome is mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G>A p.(Glu17Lys) pathogenic variant in AKT1, a variant that is also present in many cancers. Here we describe an individual with severe Proteus syndrome who died at 7 ½ years of age from combined parenchymal and restrictive pulmonary disease. Remarkably, this individual was found to harbor a mosaic c.49_50delinsAG p.(Glu17Arg) variant in AKT1 at a variant allele fraction that ranged from <0.01 to 0.46 in fibroblasts established from an overgrown digit. This variant was demonstrated to be constitutively activating by phosphorylation of AKT(S473). These data document allelic heterogeneity for Proteus syndrome. We recommend that individuals with a potential clinical diagnosis of Proteus syndrome who are negative for the p.(Glu17Lys) variant be tested for other variants in AKT1.
ObjectiveThe purpose of this project was to use an in vivo method to discover riboswitches that are activated by new ligands. We employed phage-assisted continuous evolution (PACE) to evolve new riboswitches in vivo. We started with one translational riboswitch and one transcriptional riboswitch, both of which were activated by theophylline. We used xanthine as the new target ligand during positive selection followed by negative selection using theophylline. The goal was to generate very large M13 phage populations that contained unknown mutations, some of which would result in new aptamer specificity. We discovered side products of three new theophylline translational riboswitches with different levels of protein production.ResultsWe used next generation sequencing to identify M13 phage that carried riboswitch mutations. We cloned and characterized the most abundant riboswitch mutants and discovered three variants that produce different levels of translational output while retaining their theophylline specificity. Although we were unable to demonstrate evolution of new riboswitch ligand specificity using PACE, we recommend careful design of recombinant M13 phage to avoid evolution of “cheaters” that short circuit the intended selection pressure.Electronic supplementary materialThe online version of this article (10.1186/s13104-018-3965-6) contains supplementary material, which is available to authorized users.
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