University of Oulu

Genetic factors in bone disorders : osteogenesis imperfecta, juvenile osteoporosis and stress fractures

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Author: Hartikka, Heini1,2
Organizations: 1University of Oulu, Faculty of Medicine, Department of Medical Biochemistry and Molecular Biology
2University of Oulu, Biocenter Oulu
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
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Language: English
Published: 2005
Publish Date: 2005-05-16
Thesis type: Doctoral Dissertation
Defence Note: Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium of the Medipolis (Kiviharjuntie 11), on May 26th, 2005, at 10 a.m.
Reviewer: Professor Heikki Kröger
Professor Risto Penttinen


Genetic factors and their resulting phenotypes were evaluated in three different bone disorders: osteogenesis imperfecta (OI), juvenile idiopathic osteoporosis (JIO), and stress fractures.

The spectrum of the OI phenotypes caused by mutations in the COL1A1 and COL1A2 genes is well defined, but the mechanisms by which the variations affect the hearing phenotype are not well-known. A total of 54 Finnish OI patients with previously diagnosed hearing loss, or aged 35 or more years, were analyzed here for mutations in COL1A1, or COL1A2. Altogether, 49 mutations were identified, of which 41 were novel. No correlation was observed between the mutated gene, or the mutation type, and the hearing pattern. This indicates that the basis of hearing loss in OI is complex, and is a result of multifactorial, still unknown genetic effects, or of variable expressions of the COL1A1 and COL1A2 genes.

JIO presents peri-pubertally as an acute symptomatic osteoporosis (bone pain and fractures) in otherwise healthy children, and no underlying cause has yet been identified for this disorder. Here, the analysis of the low-density lipoprotein receptor-related protein 5 gene (LRP5) in 20 patients with JIO revealed two missense mutations (A29T and R1036Q) and one frameshift mutation (C913fs) in 3 of the patients. The LRP5 gene has recently been shown to be also involved in osteoporosis-pseudoglioma syndrome and a high-bone-mass phenotype.

Stress fractures are a significant problem among athletes and soldiers. Genetic factors may increase the fracture risk, but no susceptibility genes have yet been identified. Seven genes involved in bone metabolism, or pathology, were studied in terms of their roles in stress fracture. No disease-causing, or predisposing variations were found in the candidate gene, or association analyses, but a highly significant association was found between the phenotype and a vitamin D receptor (VDR) haplotype, TGT, which is composed of three polymorphic sites, FokI, BsmI and TaqI. We showed that femoral neck stress fractures are associated with a certain VDR haplotype, accounting for a five-fold increase in the risk of developing stress fractures, with an associated attributable risk of 12%.

The results of this study show that genetic factors play a role in different pathological bone phenotypes. These findings provide new information on the pathogenesis of the disorders and for the development of genetic testing and targeted treatment for the disorders.

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Series: Acta Universitatis Ouluensis. D, Medica
ISSN-E: 1796-2234
ISBN: 951-42-7718-X
ISBN Print: 951-42-7717-1
Issue: 826
Copyright information: © University of Oulu, 2005. This publication is copyrighted. You may download, display and print it for your own personal use. Commercial use is prohibited.