A zebrafish model for Bruck Syndrome caused by PLOD2 mutations

Introduction: Bruck syndrome, which exhibits the bone fragility of OI and joint contractures, is caused by recessive mutations in either PLOD2 or FKBP10. PLOD2 is encoding the lysyl-hydroxylase 2 (LH2) enzyme, which is a collagen telopeptide lysyl hydroxylase (ref). Defective LH2 causes underhydroxylation of lysine residues within the telopeptides of type I collagen, resulting in aberrant cross-linking of bone collagen. Although the molecular role of PLOD2 has been documented, no animal models for this disease have been reported. To further elucidate the function of PLOD2 in vertebrate skeletal development, we generated a zebrafish model Method: The described plod2 nonsense mutation was generated by the Zebrafish Mutation Project (ZMP). Adult homozygous mutant zebrafish were scanned using a Triumph µCT scanner and the data was analyzed using AMIDE software in order to determine bone densities. Furthermore, the bone in fixed mutants was stained using alizarin red. Results: Preliminary results indicate that homozygous plod2 mutant zebrafish have a shortened body axis and malformed craniofacial structures. Detailed bone phenotyping using µCT and alizarin red staining revealed malformations of the skeleton including the presence of platyspondyly. Bone density measurements did not reveal a decrease in bone density. Discussion: We generated a zebrafish mutant carrying a homozygous nonsense mutation in plod2. Although preliminary, bone phenotyping revealed severe bone abnormalities with a shortened body axis and the presence of platyspondyly as the most remarkable findings, features that are also regularly detected in Bruck Syndrome patients. Therefore, this zebrafish mutant is a promising model for further unraveling the pathogenetic mechanisms leading to Bruck Syndrome. References: Ha-Vinh R, Alanay Y, Bank RA, Campos-Xavier AB, Zankl A, Superti-Furga A, Bonafe´ L (2004) Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2. Am J Med Genet A 131:115U+2013120.

Publication year:2014