Modifiers of Down Syndrome Co-occurring Phenotypes

Individuals with Trisomy 21 (Ts21) have ~80 defined clinical phenotypes collectively known as Down syndrome (DS); the incidence and severity of these phenotypes, however, are highly variable. The relationship between specific genes and phenotypes associated with DS has been studied for decades, but how modifier genes affect the incidence and variability of DS phenotypes is not well known, and only a few attempts have been made to identify two-copy or background genes that significantly modify DS phenotypes. Additionally, differences in many skeletal and neurobehavioral phenotypes have been noted between males and females with Ts21, but how sex modifies DS phenotypes has been understudied. More than twenty DS mouse models have been developed to understand gene-phenotype relationships in DS, but the inbred genetic backgrounds of all current mouse models do not offer an adequate landscape to analyze the impact of genetic diversity seen in humans with DS. Moreover, limited study of the development of sex-specific phenotypes has hampered the identification of the modifying causes of these traits. Additionally, how changes in the skeletal system may affect cognitive and behavioral functions has not been extensively investigated. Our central hypotheses are that novel, genetically robust DS mouse models will better represent the human condition and will facilitate localization of modifier genes and molecular mechanisms linked to the variable sex-specific skeletal and cognitive phenotypes associated with DS. The objectives of this project are to create new DS mouse models that better represent the variability found in the human Ts21 genetic condition, identify modifier genes and molecular pathways that lead to the variability in incidence and severity of DS skeletal and neurobehavioral traits, and determine if skeletal improvements ameliorate brain-related phenotypes in DS mice. To achieve these objectives, we will 1) create a diverse set of new DS mouse model lines to determine the overall contribution of triplicated and non-triplicated background genes on the incidence and severity of skeletal phenotypes associated with DS; 2) utilize an innovative QTL analysis of the new DS mouse model lines to identify non-triplicated modifier genes most affecting the incidence and severity of sex-specific DS skeletal phenotypes; 3) quantify modifiers of and changes skeletal and neurobehavioral measures after mechanical stimulation of bone in a selection of the new DS mouse model lines. Our proposal is significant because it establishes methodology to define gene-phenotype relationships for any DS phenotype, quantifies mechanisms of modifying gens, and determines if there is a link between abnormal DS skeletal development and functional brain deficits. This innovative work is in response to the NIH INCLUDE (INvestigation of Co- occurring conditions across the Lifespan to Understand Down syndromE) request for new DS mouse models to better define the pathophysiological effects of Ts21 and proposes a high-risk basic science study of the co- occurring bone and brain traits to identify genetic pathways that may be most responsive to new DS therapies. Project Number: 1R01HD118475-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: RANDALL ROPER | Institution: INDIANA UNIVERSITY INDIANAPOLIS, INDIANAPOLIS, IN | Award Amount: $1,303,054 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IVBH-A (57)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11847501