Reduced secretion of structurally abnormal type I procollagen in a form of osteogenesis imperfecta.

Abstract

Osteogenesis imperfecta is a clinically and genetically heterogeneous group of inherited connective tissue disorders in which bone fragility is the predominant feature. Cultured dermal fibroblasts from one patient with the lethal perinatal form ofosteogenesis imperfecta secrete type I procollagen at a rate half that of normal cells. Short-term labeling experiments and treatment with a,a'-dipyridyl (which prevents posttranslational prolyl and lysyl hydroxylation) demonstrated that these cells produce two distinct proal(I) chains, which are synthesized at the same rate. Analysis of cyanogen bromide peptides indicated that the two chains differ in their primary structures. Thus, structural abnormalities in type I procollagen prevent this molecule from being secreted normally, resulting in an anomalously low ratio of type I procollagen to other extracellular matrix molecules. While the lethal perinatal form of osteogenesis imperfecta may be heterogeneous, we propose that the underlying pathogenesis of at least one form is decreased secretion of type I procollagen.Osteogenesis imperfecta (01) is a heterogeneous group of heritable disorders in.which osseous fragility is the common feature (1). The inheritance pattern, the frequency of bone fractures, and the involvement of tissues other than bone have provided the basis for a recent classification that distinguishes four groups of01 (2). Additional genetic and biochemical heterogeneity may exist within some or all of these groups (3, 4). Abnormalities in the metabolism ofcollagen (5-10), glycosaminoglycans (11)(12)(13), and proteoglycans (14) have all been proposed to account for the clinical findings in 01, but the primary biochemical defect in each form remains unknown.The most severe form of 01 is type II, also known as the congenital crumpled bone or lethal perinatal variety (2). Affected infants have major abnormalities in bone formation and extremely friable connective tissue (15). The distribution of clinical findings corresponds to the distribution of type I collagen in tissues (16), and decreased production of type I collagen has been observed in cells from a patient with lethal perinatal 01 (6, 17).The pathway of collagen biosynthesis is complex, and several alterations could lead to decreased production oftype I collagen (18,19). In reexamining cultured cells derived from a well-studied patient (6,14,15,17,20) with lethal perinatal 01, we have found that the type I procollagen synthesized by these cells is not secreted at a normal rate, and we suggest that failure of secretion is secondary to a structural mutation in one or both proal(I) chains. MATERIALS AND METHODSCell Culture. OI cells (CRL 1262) The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

Evaluating Children With Fractures for Child Physical Abuse

“…55 Some types of OI involve reduced production of collagen, and the symptoms resolve or lessen after puberty. 56 Table 2 lists the various signs and symptoms that can be present in a case of OI.…”

“…55 Some types of OI involve reduced production of collagen, and the symptoms resolve or lessen after puberty. 56 Table 2 lists the various signs and symptoms that can be present in a case of OI.The diagnosis of OI is often suggested by a family history of fractures, short stature, blue sclera, poor dentition, and radiographic evidence of low bone density or osteopenia. The fractures are most commonly transverse in nature, occurring in the shafts of the long bones.…”

Gene therapy approaches for osteogenesis imperfecta

“…The genetic mutation is such that synthesis of normal type I collagen occurs, but in reduced amounts due to a null a1(I) allele. 12,13 Type II OI is the most severe form with most resulting in prenatal fatality. Infants with Type II OI experience intrauterine fractures, intracranial hemorrhage following vaginal delivery and succumb to death shortly after birth.…”

Evaluating Infants and Young Children With Multiple Fractures

“…4 Some types of osteogenesis imperfecta involve slow production of collagen, and the symptoms resolve or lessen after bone growth stops. 5 In addition, spontaneous mutations are common, so there may be no family history of bone disease. Table 1 lists the various signs and symptoms that can be present in a case of osteogenesis imperfecta.…”