Genetic causes and mechanisms of Osteogenesis Imperfecta

Abstract

Osteogenesis Imperfecta (OI) is a genetic disorder characterized by various clinical features including bone deformities, low bone mass, brittle bones, and connective tissue manifestations. The predominant cause of OI is due to mutations in the two genes that encode type I collagen. However, recent advances in sequencing technology has led to the discovery of novel genes that are implicated in recessive and dominant OI. These include genes that regulate the post-translational modification, secretion and processing of type I collagen as well as those required for osteoblast differentiation and bone mineralization. As such, OI has become a spectrum of genetic disorders informing about the determinants of both bone quantity and quality. Here we summarize the known genetic causes of OI, animal models that recapitulate the human disease and mechanisms that underlie disease pathogenesis. Additionally, we discuss the effects of disrupted collagen networks on extracellular matrix signaling and its impact on disease progression.

Genetic Burden Contributing to Extremely Low or High Bone Mineral Density in a Senior Male Population From the Osteoporotic Fractures in Men Study (MrOS)

“…Recent preclinical studies not only show these genes important in determining bone mass via alteration of TGF-β signaling, (32) but also potentially bone quality via crosslinking defects. (33)(34)(35) Also of note, the EDS gene set showed significant associations with low BMD, which is compatible with the clinical observation that cohorts of EDS patients displayed significantly increased prevalence of vertebral fractures. (36)(37)(38) Of the EDS genes we examined, SLC39A13 and B4GALT7 are known to cause spondylodysplastic EDS, where short stature and pathognomonic radiological findings were included as the diagnostic criteria.…”

“…Interestingly, these AR OI disease trait genes encode for collagen modification enzymes that are associated with collagen hydroxylation, glycosylation, and ultimately, crosslinking. Recent preclinical studies not only show these genes important in determining bone mass via alteration of TGF‐β signaling, but also potentially bone quality via crosslinking defects …”

Efficacy of teriparatide vs neridronate in adults with osteogenesis imperfecta type I: a prospective randomized international clinical study

“…Although most cases of OI are caused by COLIA1/ A2 mutations, many new genetic causes have been identified in recent years. Some of these genes are related to the processing of type 1 collagen (17). An important part of managing OI and staying healthy is assembling a good health care team and having a solid working relationship with primary care doctor and medical specialists.…”

Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research

“…The majority of individuals with OI have a disease‐causing mutation in one of the two genes that code for collagen type I alpha chains, COL1A1 and COL1A2 . Collagen type I is the main component of the organic bone matrix and therefore plays a key role in the integrity of bone tissue . Mutations in 18 genes other than COL1A1 and COL1A2 have been associated with OI phenotypes and are listed in the OI mutation database (https://oi.gene.le.ac.uk).…”