Novel Disease Genes Underlying Rare Recessively Inherited Forms Of Osteogenesis Imperfecta

Abstract

Osteogenesis imperfecta (OI) is a rare inherited connective tissue disorder affecting bone. Defining features are fragile bones that are highly susceptible to fracture (“brittle bone”) and bone deformation. There is a high degree of variability in the clinical skeletal features of OI, even sometimes within families. Presentations range on a spectrum from mild with few fractures, normal stature, and normal life expectancy to severe with intrauterine fractures and disrupted skeletal development leading to early lethality. Variability in a number of extraskeletal features is also observed. The underlying cause of OI has long been understood to be defects in type I collagen, the most abundant protein component of bone, tendon, and ligaments. Variants in the primary collagen genes COL1A1 and COL1A2 are the cause of OI in the majority of affected individuals in an autosomal dominant fashion and affect the quantity or quality of type I collagen molecules. In the last decade, very rare cases of OI have been identified that are caused by variants in a growing list of genes (IFITM5, SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, SP7, BMP1, TMEM38B, WNT1, CREB3L1, SPARC, MBTPS2, MESDC2) with a diversity of roles in collagen and bone biology, almost all of which are recessively-inherited conditions. The work presented in this dissertation reflects contributions to this relatively new awareness in the OI community including: 1) the second case of CREB3L1-associated OI reported in the literature; 2) exploration of the pathogenic mechanism of CREB3L1-associated OI using human induced pluripotent stem cell (hiPSC) in vitro OI disease models; and 3) report of the first identified OI-causing variants in MESDC2. This work emphasizes the importance of cellular secretion and WNT signaling pathways in bone development and may be the basis of advances in further disease gene discovery, in drug development, and in the creation of novel therapeutics for OI and related conditions.