Dissecting the phenotypic variability of osteogenesis imperfecta

Abstract

Osteogenesis imperfecta (OI) is a heterogeneous family of collagen type I-related diseases characterized by bone fragility. OI is most commonly caused by single-nucleotide substitutions that replace glycine residues or exon splicing defects in the COL1A1 and COL1A2 genes that encode the α1(I) and α2(I) collagen chains. Mutant collagen is partially retained intracellularly, impairing cell homeostasis. Upon secretion, it assembles in disorganized fibrils, altering mineralization. OI is characterized by a wide range of clinical outcomes, even in the presence of identical sequence variants. Given the heterotrimeric nature of collagen I, its amino acid composition and the peculiarity of its folding, several causes may underlie the phenotypic variability of OI. A deep analysis of entries regarding glycine and splice site collagen substitution of the largest publicly available patient database reveals a higher risk of lethal phenotype for carriers of variants in α1(I) than in α2(I) chain. However, splice site variants are predominantly associated with lethal phenotype when they occur in COL1A2. In addition, lethality is increased when mutations occur in regions of importance for extracellular matrix interactions. Both extracellular and intracellular determinants of OI clinical severity are discussed in light of the findings from in vitro and in vivo OI models. Combined with meticulous tracking of clinical cases via a publicly available database, the available OI animal models have proven to be a unique tool to shed light on new modulators of phenotype determination for this rare heterogeneous disease.

Keywords: Bone; Osteogenesis imperfecta; Phenotypic variability.

Fig. 1.

Lethal regions in collagen type I. (A) Exons containing glycine substitutions (red) and splice variants (blue) in COL1A1 (top) and COL1A2 (bottom) that are associated with phenotypic variability. Exons of which variants have been identified in >20 affected individuals are indicated by a darker shade of red and blue. Exons without reported sequence variants are in white for COL1A1 and in grey for COL1A2. (B) Structure of collagen type I protein showing the regions associated with lethal mutations in α1(I) in red.

Fig. 2.

Distribution of collagen type I sequence variants in α1(I) and α2(I) chains, type/position of the variants and nature of the substituting amino acid in osteogenesis imperfecta (OI). (A) Overall distribution of sequence variants in collagen I chains. (B) Distribution of glycine substitutions and splice site sequence variations in the α1(I) and α2(I) chains of collagen I. Glycine substitutions are shown in red, splice site mutations are shown in blue. (C) Distribution of splice site sequence variants along the COL1A1 and COL1A2 genes. (D) Distribution of glycine (Gly) substitution sequence variants along the α1(I) and α2(I) chains. (E) Distributions of bulkier amino acids substituting glycine in the α1(I) and α2(I) chains, resulting in structure alterations. These panels summarize data from our new analysis of the public COL1A1 and COL1A2 sequence variant databases. We focus on OI causative variants that affect the triple-helix region of collagen type I. COL1A1: https://databases.lovd.nl/shared/genes/COL1A1; COL1A2: https://databases.lovd.nl/shared/genes/COL1A2.

Fig. 3.

Effects of collagen type I sequence variants in α1(I) and α2(I) chains on OI lethality. (A) Overall distribution of sequence variants in collagen I chains that cause lethal OI. (B) Distribution of lethality between glycine substitution and splice site sequence variants in α1(I) and α2(I) chains. (C) Frequencies of lethal outcomes associated with splice site sequence variants along the COL1A1 and COL1A2 genes. (D) Frequencies of lethal outcomes associated with glycine substitutions along the α1(I) and α2(I) chains. (E) Distributions of glycine-substituting amino acids in α1(I) and α2(I) chains that are associated with a lethal outcome. These panels summarize data from our new analysis of the public COL1A1 and COL1A2 sequence variant databases. We focus on OI causative variants that affect the triple-helix region of collagen I. COL1A1: https://databases.lovd.nl/shared/genes/COL1A1; COL1A2: https://databases.lovd.nl/shared/genes/COL1A2.

Fig. 4.

Patient database records and animal models shed light on phenotypic variability of osteogenesis imperfecta (OI): insights on prognosis and new targets for therapy. OI is a rare disease with variable severity. To understand the complex genotype–phenotype relationship in OI, researchers combine information from human mutation databases, and available zebrafish and murine OI models carrying dominant mutations in collagen I genes to dissect the contributions of extra- and intracellular factors to disease severity. These include non-collagen components of the extracellular matrix, as well as cellular and molecular processes, such as post-translational modifications (PTM), the unfolded protein response (UPR), and autophagy and cytoskeleton dynamics. These research efforts combined to understand phenotypic variability will improve OI prognosis and allow the identification of novel therapeutic targets.