Bone Abstracts

Osteogenesis imperfecta (OI) is a genetic disorder, leading to fragility of the bones. The clinical variability is extreme, ranging from relatively mild to perinatally lethal. Secondary features such as short stature, blue sclerae, dentinogenesis imperfecta and hearing loss may also exist in affected individuals. OI is most often caused by mutations in the collagen type I genes COL1A1 and COL1A2, that show a dominant mode of inheritance. The least severe OI cases are usually caused by a reduction in the production of collagen type I protein, due to an effective null allele or deletion of one allele of COL1A1, leading to haploinsufficiency. The more severe forms of OI are often caused by missense mutations in the type I collagen genes, that affect the formation of the triple helix of the collagen type I protein. Incorporation of aberrant collagen in the extracellular matrix leads to a dominant negative effect.

In recent years, several genes have been discovered that convey recessive forms of OI. Many of these genes encode proteins, involved in processing, modification or transport of type I collagen.

In our laboratory, some 25% of the >1200 OI cases that were tested by DNA analysis were negative for mutations in all known OI causing genes. So it is evident that several hitherto unknown genes are involved in OI. These will most likely be identified by exome sequencing in the near future.

Severe OI is evident at birth, but milder cases may not be noticed immediately. Therefore, in young children, OI may lead to suspicion of non-accidental injury, which may have devastating effects on families. Differential diagnosis, based on radiological and molecular findings, is essential in cases of suspected child abuse, if suspicion is mainly based on recurrent unexplained fractures.

The primary defect in most OI cases is the production of insufficient amounts of collagen type I, or deposition of structurally abnormal collagen type I in the extracellular matrix. Collagen fibers in the correct orientation are essential for proper bone mineralization. The therapy that is currently used is based on bisphosphonate inhibition of osteoclasts to reduce bone turnover. This leads to reduction of bone fragility by increasing the bone mineral density, but the resulting harder bone is still brittle. Bisphosphonate therapy does not target the primary defect of reduced, or structurally abnormal collagen. Long term administering of these drugs may eventually have adverse effects, such as complete loss of osteoclasts. Consequently, new therapeutic targets are needed for OI.