Osteogenesis imperfecta is a group of rare connective tissue disorders characterized by extremely fragile bones that fracture easily; often without any external force. It is caused due to the failure of maturation and organization of collagen fibers, decreased collagen secretion, or defect in osteoblastic function. Osteogenesis imperfecta is currently classified into seven types based on differences in clinical presentation and bone architecture.
Type I osteogenesis imperfecta tends to be milder than the other types of osteogenesis imperfecta and is most common type of the disorder occurring with a frequency of about 1 in 15,000 to 20,000 people. It is usually transmitted as an autosomal dominant trait with variable penetrance. The clinical manifestations of the disorder can be skeletal (bone fragility, hyperextensible joints and ligaments), cutaneous (thin and translucent skin), ocular (keratoconus, megalocornea), and dental (hypoplasia of dentin and pulp). Hearing loss occurs in at least half of people with type I osteogenesis imperfecta, usually beginning in the late teens or early adulthood. Decreased hearing is usually caused by problems with the middle ear bones (conductive hearing loss), but in some cases the inner ear and the auditory nerve also become involved (mixed conductive and sensorineural hearing loss). Inguinal and umbilical hernia secondary to poor muscular development, capillary fragility, small stature with short limbs, and triangular-shaped head, may occur.
More than 90% of individuals with osteogenesis imperfecta have mutations in one of the two genes - COL1A1 and COL1A2, which encode the chains of type I procollagen, the major protein in bone and most other connective tissues. The two general outcomes of these mutations are either a decrease in the amount of type I procollagen produced or the production of abnormal type I procollagen molecules.
In most instances, osteogenesis imperfecta type I results from mutations in the COL1A1 gene that result in premature termination codons. The presence of a premature termination codon in the gene leads to marked instability of the mRNA derived from the mutant allele. Consequently, the amount of COL1A1 mRNA is reduced to half the normal amount, with no compensation by the other allele. Type I procollagen is a trimer that must contain at least two pro alpha1 chains. With a reduction in the COL1A1 mRNA, an obligatory decrease in the production of type I procollagen occurs, although, the protein produced is structurally normal. The diminished amount of type I collagen in bone affects its development and strength resulting in the formation of brittle bones.
