The collagen VI-related myopathies: muscle meets its matrix

Abstract

The collagen VI-related myopathy known as Ullrich congenital muscular dystrophy is an early-onset disease that combines substantial muscle weakness with striking joint laxity and progressive contractures. Patients might learn to walk in early childhood; however, this ability is subsequently lost, concomitant with the development of frequent nocturnal respiratory failure. Patients with intermediate phenotypes of collagen VI-related myopathy display a lesser degree of weakness and a longer period of ambulation than do individuals with Ullrich congenital muscular dystrophy, and the spectrum of disease finally encompasses mild Bethlem myopathy, in which ambulation persists into adulthood. Dominant and recessive autosomal mutations in the three major collagen VI genes—COL6A1, COL6A2, and COL6A3—can underlie this entire clinical spectrum, and result in deficient or dysfunctional microfibrillar collagen VI in the extracellular matrix of muscle and other connective tissues, such as skin and tendons. The potential effects on muscle include progressive dystrophic changes, fibrosis and evidence for increased apoptosis, which potentially open avenues for pharmacological intervention. Optimized respiratory management, including noninvasive nocturnal ventilation together with careful orthopedic management, are the current mainstays of treatment and have already led to a considerable improvement in life expectancy for children with Ullrich congenital muscular dystrophy.

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

“…Animals null for COL6A1 show a marked improvement in heart function and decreased scarring following left anterior descending (LAD) ligation, as in the case of WNT-974-treated animals. Similar to other collagen proteins, a Col6 monomer comprises three subunits (Col6a1, -a2, -a3) that are assembled in stoichiometric fashion in the secretory pathway (24). Recessive mutations associated with Ullrich congenital muscular dystrophy found in a single subunit of Col6 are sufficient to eliminate the production of Col6 microfibrils, thus revealing the importance of coordinated subunit expression (24).…”

“…Similar to other collagen proteins, a Col6 monomer comprises three subunits (Col6a1, -a2, -a3) that are assembled in stoichiometric fashion in the secretory pathway (24). Recessive mutations associated with Ullrich congenital muscular dystrophy found in a single subunit of Col6 are sufficient to eliminate the production of Col6 microfibrils, thus revealing the importance of coordinated subunit expression (24). Notably, among the collagen gene family members including those abundantly expressed in heart tissue, such as Col1 and Col3, the expression of Col6a3 was the most impacted by the presence of WNT-974 (Fig.…”

COL6A3 Protein Deficiency in Mice Leads to Muscle and Tendon Defects Similar to Human Collagen VI Congenital Muscular Dystrophy

“…Mutations of the COL6A1, COL6A2, and COL6A3 genes encoding the ␣1(VI), ␣2(VI), and ␣3(VI) collagen chains underlie Bethlem myopathy, Ullrich congenital muscular dystrophy, and phenotypes intermediate between Ullrich congenital muscular dystrophy and Bethlem myopathy (14,15). The signature features of collagen VI-related muscle disorders are early onset muscle weakness in conjunction with connective tissue abnormalities.…”

Sarcolemmal Specific Collagen VI Deficient Myopathy in a Labrador Retriever

“…Clinical signs of collagen VI deficiency in people can vary from severe muscle weakness with axial and proximal contractures and distal joint hyperlaxity in Ullrich's congenital muscular dystrophy (UCMD) to moderate or mild muscle weakness and distal joint contractures in Bethlem myopathy (BM). Patients with UCMD might never acquire the ability to move independently or lose this ability between the first and second decade of life, concomitant with the development of frequent respiratory failure caused by the involvement of the diaphragm 6. Patients with intermediate phenotypes have a lesser degree of weakness and a longer period of ambulation than UCMD, but are more severely affected than patients with BM, the mildest form of collagen VI‐related myopathy, characterized by slowly progressive axial and proximal muscle weakness with distal joint contractures 6…”

“…Mutations in the three collagen VI genes COL6A1, COL6A2, and COL6A3 , have been associated with collagen VI deficiency in both the severe UCMD and the milder BM 6. Mutations in both COL6A1 and COL6A2 have been identified in some patients with SSCD; however, other patients lack mutations in collagen VI genes and a failure to anchor the basal lamina to the intersititum, possible because of mutations in other molecules has been postulated 12, 13.…”