Canine Chondrodysplasia Caused by a Truncating Mutation in Collagen-Binding Integrin Alpha Subunit 10

The skeletal dysplasias are disorders of the bone and cartilage tissues. Similarly to humans, several dog breeds have been reported to suffer from different types of genetic skeletal disorders. We have studied the molecular genetic background of an autosomal recessive chondrodysplasia that affects the Norwegian Elkhound and Karelian Bear Dog breeds. The affected dogs suffer from disproportionate short stature dwarfism of varying severity. Through a genome-wide approach, we mapped the chondrodysplasia locus to a 2-Mb region on canine chromosome 17 in nine affected and nine healthy Elkhounds (praw = 7.42610 26, pgenome-wide = 0.013). The associated locus contained a promising candidate gene, cartilage specific integrin alpha 10 (ITGA10), and mutation screening of its 30 exons revealed a nonsense mutation in exon 16 (c.2083C.T; p.Arg695*) that segregated fully with the disease in both breeds (p = 2.5610223). A 24 % mutation carrier frequency was indicated in NEs and an 8 % frequency in KBDs. The ITGA10 gene product, integrin receptor a10-subunit combines into a collagen-binding a10b1 integrin receptor, which is expressed in cartilage chondrocytes and mediates chondrocyte-matrix interactions during endochondral ossification. As a consequence of the nonsense mutation, the a10-protein was not detected in the affected cartilage tissue. The canine phenotype highlights the importance of the a10b1 integrin in bone growth, and the large animal model could be utilized to further delineate its specific functions. Finally, thi