Lethal osteogenesis imperfecta and a collagen gene deletion. Length polymorphism provides an alternative explanation

Summary A 300 base pair deletion near the 3-end of the gene encoding Type II (cartilage) collagen has been implicated in the pathogenesis of perinatal lethal osteogenesis imperfecta. We have found similar deletions occurring at a high frequency in normal Asian Indian and West Indian populations generated by a length polymorphism just beyond the 3-end of the gene. We suggest that this polymorphism provides an alternative explanation of the original results.     

Lethal osteogenesis imperfecta. Definition and heterogeneity

The lethal form of osteogenesis imperfecta must be more clearly defined than it is. Early death of the child is not a sufficient criteria since it is observed in other forms compatible with survival. The authors therefore insist on the innumerable fractures of the ribs giving the particular aspect described as "bamboo ribs". These are observed in practically all cases. Heterogeneity however is undoubtful and an X-ray film is reproduced showing thin ribs without fractures in another exceptional lethal form. Genetic and very recent biochemical investigations suggest a new heterogeneity of the lethal form, even well defined clinically and radiologically. Contrary to earlier and frequent statements, it results most often from a dominant mutation, while recessive inheritance is much rarer, therefore the overall risk of recurrence much below 25%.     

Lethal osteogenesis imperfecta congenita and a 300 base pair gene deletion for an alpha 1(I)-like collagen.

Broad boned lethal osteogenesis imperfecta is a severely crippling disease of unknown cause. By means of recombinant DNA technology a 300 base pair deletion in an alpha 1(I)-like collagen gene was detected in six patients and four complete parent-child groups including patients with this disease. One from each set of the patients'' clinically unaffected parents also carried the deletion, implying that affected patients were genetic compounds. The study suggests that prenatal diagnosis should be possible with 100% accuracy in subjects without the deletion and with 50% accuracy in those who possess it (who would be either heterozygous--normal, or affected with the disease).     

Multiexon deletion in an osteogenesis imperfecta variant with increased type III collagen mRNA

Recently, the dermal fibroblasts (ATCC CRL 1262) of a lethal perinatal variant of osteogenesis imperfecta have been used for the first molecular characterization of a collagen gene defect (Chu, M. L., Williams, C. J., Pepe, G., Hirsch, J. L., Prockop, D. J., and Ramirez, F. (1983) Nature (Lond.) 304, 78-80). These studies revealed that the patient was heterozygous for an internal deletion of approximately 500 base pairs in the pro-alpha 1(I) collagen gene, consistent with previous investigations indicating that CRL 1262 fibroblasts equally synthesized a normal and a shortened pro-alpha 1(I) chain (Barsh, G. S., and Byers, P. H. (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 5142-5146). Cloning and analysis of the affected allele of CRL 1262 has now indicated that the deletion is contained between two introns of the pro-alpha 1(I) gene and results in the elimination of three exons of the triple helical domain. Furthermore, the termini of the rearrangement are located within two short inverted repeats suggesting that the self-complementary nature of these DNA elements may have favored the formation of a DNA secondary structure intermediate which, in turn, served as substrate for the deletion. Evidence are also presented for an elevated Type III collagen mRNA content in the patient fibroblasts.     

A 9-base pair deletion in COL1A1 in a lethal variant of osteogenesis imperfecta

A proband with lethal osteogenesis imperfecta has been investigated for the causative defect at the levels of collagen protein, mRNA, and DNA. Analysis of type I collagen synthesized by the proband's fibroblasts showed excessive post-translational modification of alpha 1(I) chains along the entire length of the helix. Oververmodification of alpha chains could be prevented by incubation of the cells at 30 rather than 37 degrees C, and the thermal stability of the triple helix, as determined by protease digestion, was normal. RNase A cleavage of RNA:RNA hybrids formed between the proband's mRNA and antisense RNA derived from normal pro-alpha 1(I) chain cDNA clones was used to locate an abnormality to exon 43 of the proband's pro-alpha 1(I) collagen gene (COL1A1). The nucleotide sequence of the corresponding gene region showed, in one allele, the deletion of 9 base pairs, not present in either parent, within a repeating sequence of exon 43. The mutation causes the loss of one of three consecutive Gly-Ala-Pro triplets at positions 868-876, but does not otherwise disrupt the Gly-X-Y sequence. Procollagen processing in fibroblast cultures and susceptibility of the mutant collagen I to cleavage with vertebrate collagenase were normal, indicating that the slippage of collagen chains by one Gly-X-Y triplet does not abolish amino-propeptidase and collagenase cleavage sites. How the mutation produces the lethal osteogenesis imperfecta phenotype is not entirely clear; the data suggest that the interaction of alpha chains immediately prior to helix formation may be affected.     

A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a hereditary bone disease characterized by decreased bone density and multiple fractures, usually inherited in an autosomal dominant manner. Several gene encoding proteins related to collagen metabolism have been described in some cases of autosomal recessive OI (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10). Recently, TMEM38B, a gene that encodes TRIC-B, a monovalent cation-specific channel involved in calcium flux from intracellular stores and in cell differentiation, has been associated with autosomal recessive OI. Here, we describe the second deletion-mutation involving the TMEM38B gene in an 11 year-old Albanian female with a clinical phenotype of OI, born to parents with suspected consanguinity. SNP array analysis revealed a homozygous region larger than 2 Mb that overlapped with the TMEM38B locus and was characterized by a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene.     

Congenital osteogenesis imperfecta in three sibs

Summary Three sibs of a Turkish family were affected with lethal congenital osteogenesis imperfecta (OI). The disease was characterized by extremely fragile bones and crumpled femora, but in contrast to reported cases of OI type II, relatively normal ribs with only few fractures. The children affected died shortly after birth. Although their parents both came from the same small village in Turkey, consanguinity could not be demonstrated. Our observations support that this disorder is inherited in an autosomal recessive mode. We consider the possibility that these patients represent either a new subgroup of OI type II (milder, although still lethal) or of type III (more severe).This investigation was supported in part by research grants from the Deutsche Forschungsgemeinschaft.     

Emerging therapeutic approaches for osteogenesis imperfecta

Osteogenesis imperfecta (OI) is an incurable genetic brittle-bone disease. Although drug therapy, surgery and physiotherapy represent current treatments for OI, the search is ongoing for effective and innovative new therapies targeting the underlying causes of the disease. In this regard, recent advances in the fields of gene and stem-cell therapies have been considerable. In spite of the many challenges that remain, potential new therapies for OI, which have been tested in cell culture systems, animal models and patients, offer hope for the future development of successful therapies. Recent progress in the field is reviewed here.     

Psychosocial aspects of osteogenesis imperfecta.

Osteogenesis imperfecta is a heterogeneous group of inherited disorders characterized by bone fragility and recurrent fractures. It is currently classified into four types on clinical grounds and appears to arise from different disorders of bone collagen synthesis. The biochemical identification of disturbances in collagen metabolism and the genetic delineation of new mutations of collagen genes have made prenatal diagnosis by molecular methods feasible in some cases. Most people with osteogenesis imperfecta suffer frequent fractures (and sometimes consequent serious disability), for which there are few effective preventive measures. This disorder may have a profound psychosocial influence on patients and their families. In this report the extent of this influence is reviewed and aspects important to the medical community are highlighted; these include the emotional burdens imposed by unfounded suspicions of child abuse, the social and financial costs of repeated hospitalization and immobility, and the frustrations generated by the lack of helpful, practical information for families and health care workers. An important social outcome has been the rise of self-help organizations, exemplified by the Canadian Osteogenesis Imperfecta Society. For Canadian families the society has been an important vehicle for exchange of information and an active, positive response to a lifelong, often severely disabling disorder.     

Heterozygosity for a large deletion in the alpha 2(I) collagen gene has a dramatic effect on type I collagen secretion and produces perinatal lethal osteogenesis imperfecta

We characterized a de novo 4.5 kilobase pair deletion in the paternally derived alpha 2(I) collagen allele (COL1A2) from a patient with perinatal lethal osteogenesis imperfecta. The intron-to-intron deletion removed the seven exons which encode residues 586-765 of the triple helical domain of the chain. Type I procollagen molecules that contain the mutant pro-alpha 2(I) chain have a lower than normal thermal stability, undergo increased post-translational modification amino-terminal to the deletion junction, and are retained within the rough endoplasmic reticulum. The block to secretion appears to result from improper assembly of the triple helix, apparently a consequence of a disruption of charge-charge interactions between the shortened pro-alpha 2(I) chain and normal pro-alpha 1(I) chains. The lethal effect may be due to decreased secretion of normal collagen and secretion of a small amount of abnormal collagen that disrupts matrix formation.     

Strangulated diaphragmatic hernia in a patient with osteogenesis imperfecta.

Hernias are common in patients with osteogenesis imperfecta, but to our knowledge there have been no reports of diaphragmatic hernias in such patients. We describe a patient with osteogenesis imperfecta in whom a diaphragmatic hernia contained a strangulated segment of the splenic flexure of the colon. Resection of the necrotic tissue and transverse colostomy resulted in an uneventful recovery.