O.2 Collagen type XII: A new congenital matrix and muscle disease

In a small proportion of patients with an Ullrich-like clinical phenotype no mutations in the collagen VI genes are detected. Here we report on a novel muscle and tendon collagenopathy caused by mutations in COL12A1. In a consanguineous family with hypotonia, weakness and significant joint hyperlaxity we identified a homozygous frame shifting mutation in COL12A1 in the two affected children, causing complete absence of collagen XII in muscle and fibroblasts. Patients were unable to walk and developed scoliosis and respiratory insufficiency. In the second family the proband presented with milder hypotonia, motor delay, hyperlaxity and incomplete deficiency of collagen XII. We identified a de novo, presumably dominantly acting missense mutation. COL12A1 encodes collagen XII. Collagen XII is a homotrimer found in association with collagen I and acts as a cross-bridge between collagen fibrils while also interacting with tenascin X (TNX), heparin and decorin. We next investigated the muscle phenotype in a Col12a1 KO mouse, which showed age dependent weakness. At 9 months of age there was no significant difference in muscle fiber size, but the overall weight of the muscles was less with an altered slow-to-fast fiber type transition in both soleus and tibilias anterior muscles. Physiological measurements on isolated EDL showed protection from eccentric force drop and a decrease in passive force, suggesting an increased compliance of the matrix as well as decreased lateral and longitudinal force transmission to the matrix and tendon. We hypothesize that the functional abnormalities seen in muscle force measurement in COL12 KO mice originate at least partly from an underlying tendon and matrix pathology caused by the absence of collagen XII.