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Investigating mouse motor activity and learning behavior using quantitative trait locus (QTL) analysis to elucidate the genetic underpinnings of developmental coordination disorder (DCD)

University of British Columbia

Developmental coordination disorder is a neuromotor disability of unknown etiology that affects 5–6% of school-aged children. A major hallmark of DCD is difficulty in motor learning, as children with DCD struggle with learning new skills, planning of movement, adapting to change, and automatizing motor patterns. Evidence suggests DCD is highly heritable and phenotypically heterogeneous; however, little is known about the genetic basis of DCD. Hence, this study aims to investigate motor behaviors that reflect the core symptoms of human DCD in BXD recombinant inbred strains of mice and correlate phenotypic traits to the known genotypes of the lines of BXD mice using sophisticated bioinformatic tools in the hopes of finding underlying genetics of the disorder. A total of 12 different BXD inbred lines and the two parental strains (B6 and DBA) were phenotypically examined. We conducted three phases of phenotyping: a neurodevelopmental battery post-natal day (P1-P15), general motor testing (P60-P81), and a motor learning battery (P90-P120), designed to focus on similarities to the symptomology of the human condition of DCD. To date, we have found nine statistically significant QTLs and several suggestive QTLs associated with our measures of general and skilled motor function, which are defined at a particular chromosomal locus within a 1.5 LOD support interval of the QTL. Of 304 genes, we identified 14 candidate genes based on expression, function and polymorphisms within the mapped QTL intervals. Of these 14 candidates, four genes (Cp1x1, Idua, Nrip1, Ltn1) were classified as priority genes that met all our criteria and were believed to have the highest impact on phenotype. To date, no connections have been found between these candidate genes and DCD-related pathogenesis. However, we have identified overlapping loci with previously reported phenotypic data within our mapped QTL interval of motor phenotypes. The findings of this study provide novel insights into genes that may influence DCD-like motor behavior. In the long term, uncovered genes with associated variation in motor phenotypes could provide insights into genetic factors underlying DCD in the human population and help provide opportunities for early and tailored intervention in children at risk for developmental difficulties.

Text

2024-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/74768

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/