Humanized LMNA Animal Model for Detecting Pathogenicity in Clinical Variants

SUMMARYThe goal of this RSBIR grant application is to understand the role of genetic variation in LMNAFor cliniciansthe functional significance ofof the variations in LMNA have the status of being either unknown or a Variants of Uncertain SignificanceVUSAs genomic sequencing continues its expanded utilization into the clinicdiagnostic rates will improves as variant function becomes better assigned to either pathogenic or benign statusAnimal models have consistently been used as a proxy to understanding variant functionThis proposal uses expression of a LMNA cDNA as a gene substitution of the orthologous gene of Celegans animal modelWithof human genes having an identifiable homology in Celegansthe extension of this humanization process to thousands of genes is possibleThis proposal has three specific aimsThe first aim is find a recoded version of the human LMNA cDNA that can be insert as a replacement of the orthologous Celegans lmngene and exhibit a capacity to rescue the function absent in the null alleleIn the second aimknown pathogenic and benign variants are installed in the humanized locus and activity defects of the installed variants are measuredIn the third aimvariants of uncertain significance and unknown status are installed in the humanized locus and measured for deviance of activityIn future Phase II workonce variant functional behavior is measureddrug activity can be explored for capacity to reverse phenotypes back to wildtype behavior NARRATIVEThis work supports the creation of transgenic model organisms as a tool for understanding genetic variation in the human populationThe data acquired from the animal models provides information relevant to the personalized medicine of patients with rare diseaseClinicians and researchers can use the resulting disease gene information to develop new drugs and improve drug delivery for their patients