Recessive Forms of Osteogenesis Imperfecta (OI) and Implications for Mechanisms of Disease

More than 90% of people with OI are heterozygous for mutations in one of the type I collagen genes (COL1A1 and COL1A2). The mutations affect the production and structure of type I procollagen. In the last decade, studies of animal models, analysis of candidate genes, and whole exome analysis identified 11 genes in which biallelic mutations result in recessively inherited forms of OI. The genes affect 1) collagen folding and processing (CRTAP, LEPRE1, PPIB, SERPINH1, PLOD2, FKBP10 and BMP1), 2) calcium homeostasis in the RER (TMEM38B), 3) recruitment of cells to the osteoblastic pathway (SP7, WNT1), and 4) response to accumulation of abnormal proteins (CREB3L1). The clinical outcome of these mutations ranges from lethal in the perinatal period to a moderate severity and clinical signs are often difficult to distinguish from those encountered in individuals with mutations in type I collagen genes. While it is clear that the list of genes that harbor causative mutations that result in OI is incomplete, it has been thought that the diverse nature of the newly recognized recessive OI genes would provide insights into common pathways from genotype to phenotype. The most recent to emerge is the concept of disturbed TGFβ‐signaling as a consequence of accumulation of abnormal molecules in the matrix, stress in the secretory pathway, or both (see Grafe et al, Nat Med 20:670, 2014). Thus the possibility of a common, potentially treatable, aberrant pathway is an, at last hopeful, sign.