Electronic Thesis and Dissertation Repository


Doctor of Philosophy




Dr. Nathalie Berube


Alpha-thalassemia X-linked mental retardation (ATR-X) syndrome is a rare genetic disorder associated with severe developmental delay, mental retardation and craniofacial dysmorphism. This syndrome is caused by mutations in the ATRX gene which encodes a member of the SWI/SNF family of chromatin remodeling proteins. ATR-X patients exhibit dwarfism and skeletal defects, including hand and foot deformities. I hypothesized that the skeletal deformities in ATR-X syndrome are due to a direct role of ATRX in the development of the skeleton. My objective was to characterise skeletal phenotypes observed in three animal models conditionally deficient for ATRX in different skeletal tissues. Mice lacking the Atrx gene in forelimb mesenchyme, cartilage, or bone were generated using the Cre-lox system with Cre-recombinase under control of Prx1, Col2a1 or Col1a2 promoters, respectively. Mice lacking ATRX in cartilage or bone displayed limited skeletal phenotypes and did not recapitulate the defects seen in ATR-X syndrome. Loss of ATRX protein earlier during limb development lead to shortening of the distal phalanges which correlated with increased DNA damage and apoptotic cell death in the mesenchyme of developing digits. This phenotype resembles brachydactyly in human ATR-X syndrome patients and suggests that ATRX is involved in maintaining genome integrity in limb tissue. Aging mice lacking ATRX in skeletal tissues did not show any increased susceptibility to osteoarthritis. In summary, this study suggests that skeleton-intrinsic roles of ATRX are responsible for some but not all of the skeletal deformities observed in ATR-X syndrome.