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The Identification and Characterization of Chondrodysplasias Resulting from Cartilage Extracellular Matrix Abnormalities


The chondrodysplasias are a group of genetic disorders resulting from profound defects in cartilage development. Two mild chondrodysplasias, Multiple Epiphyseal Dysplasia (MED) and Stickler Syndrome (STL), result from reduced synthesis and/or altered structure of cartilage extracellular matrix (ECM) proteins, which provide a scaffold for the organization of the chondrocytes in the endochondral growth plate.

Individuals affected with MED exhibit mild short stature, joint pain, and early-onset osteoarthropathy. Dominantly inherited mutations in 5 genes, COMP, MATN3, COL9A1, COL9A2, and COL9A3, and recessively inherited mutations in SLC26A2 result in a MED phenotype, and the mutations in these genes account for the molecular basis of disease in 80-85% of the cases. Using exome sequencing, I endeavored to identify the molecular basis of the disease in cases with an unknown etiology. I identified two cases with a clinically distinct recessively-inherited form of MED due to mutations in CANT1, a gene involved in ECM biosynthesis. As this form of MED only accounts for a subset of the uncharacterized cases, there is further locus heterogeneity among patients with this phenotype.

Type IX collagen, a heterotrimeric collagenous ECM protein comprised of three procollagen chains, α1(IX), α2(IX), and α3(IX), is involved in the pathogenesis of both MED and STL. STL is characterized by mild short stature, craniofacial defects, sensorineural hearing loss, and myopia, and recessive loss-of-function mutations in all three human type IX procollagen genes have been identified in STL. Previous studies have indicated that the loss of α1(IX) results in a functional knockout of type IX collagen, but similar studies have not been conducted for α2(IX) and α3(IX). Through the generation of a Col9a2 -/- mouse, I determined that the loss of α2(IX) also results in total loss of type IX collagen, and the resulting mouse phenocopies STL.

Through the study of MED and type IX collagen, I have gained a better understanding of the mechanisms of pathogenesis in a subset of chondrodysplasias of the cartilage ECM.

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