Osteogenesis Imperfecta, an Ever-Expanding Conundrum

Abstract

Osteogenesis imperfecta (OI), or brittle bone disease, a rare heritable connective tissue disorder, was described more than a century ago. Its hallmark, bone fragility, may cause frequent fractures, spine and limb deformities, and chronic pain. Another characteristic of the OI syndrome is its wide spectrum of clinical severity, from the very mild to the lethal. Over the years, there have been several attempts at classifying the various forms of OI either by number or by degrees of severity (reviewed in Glorieux and Rowe). All such efforts have only been partially successful because, except for the extremes of the spectrum, clinical types are overlapping. Furthermore, it has been oftentimes observed that within the same family, affected subjects show a wide variation in clinical presentations. This variability in phenotype severity is matched by an ever‐ expanding genotypic variability. OI is in most cases associated with mutations in COL1A1 and COL1A2, the genes encoding type I collagen, the main component of the bone matrix. Detailed analysis of the large number of identified mutations allowed for two main groups to be delineated. The first one corresponds to mutations leading to haploinsufficiency and overall to a mild phenotype. The second group includes mutations that cause structural abnormalities in the collagen molecule compromising the organization of the bone matrix. Associated phenotypes are usually moderate to severe or, rarely, lethal. All such mutations are transmitted as autosomal dominant traits. However, in a small number (less than 10%) of OI cases, no such association could be established, and inmost of them there was evidence for autosomal recessive inheritance. In the first reported cases from a population isolate, mutations were identified in CRTAP, the gene encoding a cartilage associated protein part of the prolyl 3‐hydroxylation complex involved in the processing of the type I collagen triple helix. Subsequently, mutations were found that affected the other two subunits of the complex, prolyl 3‐hydroxylase 1 and cyclophylin B, as well as chaperones encoded by SERPINH1 and FKBP10 (reviewed in Forlino and colleagues). Thus, up to that point all abnormalities could be linked to the synthesis, secretion, processing, and matrix integration of the type I collagen molecule. Recently, other forms, where no abnormalities related to collagen type I could be elicited, were identified by detailed analysis of undecalcified bone sections obtained from iliac crest biopsies. Pathophysiologic aspects of two such entities are discussed in this issue. The first one, type V OI, was described 13 years ago. Unlike the other “new” forms of OI, it is transmitted as an autosomal dominant trait. Besides bone fragility, its main characteristics include short stature, ossification of the interosseous membrane of the forearm often leading to dislocation/subluxation of the proximal radial head, presence of radiodense bands under the growth plates, and the frequent development of hyperplastic calluses after fractures or corrective surgery. Its unique defining feature is, however, found on bone sections as a loss of the birefringent aspect of the matrix under polarized light illumination. It rather exhibits ameshlike appearance not observed in any other bone disease. Last year, two groups simultaneously reported the association of type V OI with a single identical mutation (c.‐14C> T) in the untranslated region of IFITM5. It introduces a new initiation codon that adds five residues at the N‐terminus of the gene product, an osteoblast‐specific transmembrane protein, BRIL. The findings were rapidly corroborated in a third publication, which added 42 patients to the 21 from the initial reports. Remarkably, all subjects carry the exact same mutation despite a wide variability in its phenotypic expression. Shapiro and colleagues further document this fascinating observation in an additional 17 patients. BRIL was discovered as part of a high‐throughput screen for cDNAs encoding secreted and membrane proteins in osteoblastic cells. BRIL is part of an evolutionary conserved family of so‐ called interferon‐inducible transmembrane (IFITM) proteins for which there are at least four closely related members in the human (IFITM1, 2, 3, and 10) and two others in the mouse (IFITM6 and 7). The inclusion of BRIL as part of this family is based on genomic and protein structure considerations. BRIL, IFITM1, 2, and 3 are all clustered within 25 kb on chromosome 11; they all possess a similar gene architecture comprising two small coding