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Aga2 – Additional primary phenotypes in Osteogenesis imperfecta

Source: GMC


Brittle bones, fractures and osteoporosis are symptoms of Osteogenesis imperfecta (OI), a group of inherited connective tissue disorders. Most OI cases are caused by autosomal dominant mutations in COL1A1 or COL1A2, which encode the chains of type I collagen, the most abundant protein of the extracellular matrix (ECM) of bone. Although skeletal findings are predominant, OI is a generalized connective tissue disorder as type I collagen comprises, in addition to bone, skin and tendon, 80% of lung and cardiac collagen. The non-skeletal manifestations of OI in the respiratory and cardiovascular systems are responsible for most mortality and morbidity in severe and moderate types II–IV OI, but these effects have not been directly linked to the underlying collagen mutation and have been considered secondary to skeletal changes.
In the Munich ENU mutagenesis screen, Thomas Lisse and his colleagues identified a new mouse model for OI, termed Aga2, with a dominant frameshift mutation in the Col1a1 C-propeptide domain (Thomas S Lisse, et al., ER Stress-Mediated Apoptosis in a New Mouse Model of Osteogenesis imperfect, PLoS Genet. 2008 February; 4(2): e7). Aga2 mice have OI phenotypic changes and endoplasmatic reticulum (ER) stress-related apoptosis in bone tissue. Two distinct phenotypes of Aga2 were distinguished by Christian Cohrs and Frank Thiele from the HelmholtzZentrum München: Mildly affected animals survive to adulthood (Aga2mild), while other Aga2/+ mice (Aga2severe) are postnatally lethal even with bisphosphonate administration.

The Aga2 mice were systematically phenotyped at the German Mouse Clinic (GMC). It turned out that the Aga2 type I collagen mutation directly causes pathological changes in heart and lung tissue that are bone-independent and are the primary cause of death in Aga2severe. In hearts and primary cardiac fibroblasts of Aga2severe mutant mice, the scientists observed primary structural and intrinsic cellular defects, including a strong reduction in mutant transcripts and interestingly also the wildtype Col1a1 allele. The lungs of Aga2severe mice have fracture-independent hemorrhage and inflammation throughout the tissue.
The direct relevance of the bone-independent Aga2 findings to pathogenic mechanisms in human OI is demonstrated by the findings presented here from a pediatric type III and IV OI longitudinal study population at the NICHD, NIH. The patients have collagen mutations causing severe and moderate non-lethal OI, corresponding more to non-lethal Aga2 mice (Aga2mild). Forty-six children and young adults (aged 3–23 years) with types III (progressive deforming) and IV (moderately severe) OI, most with known collagen mutations, underwent echocardiogram and ECG. 78% of the patients showed one or more cardiac defects or disruptions. Children both with and without scoliosis were shown to have clinically significant decline of pulmonary function during childhood, as well as primary cardiac valvular and chamber abnormalities

The study reports for the first time a bone-independent mechanism caused by the underlying Col1a1 mutation in the cardiopulmonary system, leading to death in the OI model Aga2. While the precise molecular mechanism has still to be elucidated, the combination of murine and pediatric OI data could lead clinicians to pay more attentive to extra-skeletal examination of OI patients and to preventive measures such as pulmonary exercise or early evaluation for nocturnal hypoxemia. Additional murine studies on pathological mechanisms may provide insights for novel therapeutic approaches.


Thiele et al., Cardiopulmonary dysfunction in the Osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms, Human Molecular Genetics, 2012, 1–11, doi:10.1093/hmg/dds183