PUBLICATION
Bmpr1aa modulates the severity of the skeletal phenotype in an fkbp10-deficient Bruck syndrome zebrafish model
- Authors
- Jarayseh, T., Debaenst, S., De Saffel, H., Rosseel, T., Milazzo, M., Bek, J.W., Hudson, D.M., Van Nieuwerburgh, F., Gansemans, Y., Josipovic, I., Boone, M.N., Witten, P.E., Willaert, A., Coucke, P.J.
- ID
- ZDB-PUB-241121-16
- Date
- 2024
- Source
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 40(1): 154-166 (Journal)
- Registered Authors
- Coucke, Paul, De Saffel, Hanna, Willaert, Andy, Witten, P. Eckhard
- Keywords
- bruck syndrome, modifier genes, phenotypic variability, skeletal disease, zebrafish models
- MeSH Terms
-
- Animals
- Arthrogryposis/genetics
- Arthrogryposis/metabolism
- Arthrogryposis/pathology
- Bone and Bones/metabolism
- Bone and Bones/pathology
- Collagen Type I/metabolism
- Disease Models, Animal*
- Humans
- Osteogenesis Imperfecta
- Phenotype*
- Tacrolimus Binding Proteins*/deficiency
- Tacrolimus Binding Proteins*/genetics
- Tacrolimus Binding Proteins*/metabolism
- Zebrafish*/metabolism
- Zebrafish Proteins*/deficiency
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 39566080 Full text @ J. Bone Miner. Res.
Citation
Jarayseh, T., Debaenst, S., De Saffel, H., Rosseel, T., Milazzo, M., Bek, J.W., Hudson, D.M., Van Nieuwerburgh, F., Gansemans, Y., Josipovic, I., Boone, M.N., Witten, P.E., Willaert, A., Coucke, P.J. (2024) Bmpr1aa modulates the severity of the skeletal phenotype in an fkbp10-deficient Bruck syndrome zebrafish model. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 40(1):154-166.
Abstract
Rare monogenic disorders often exhibit significant phenotypic variability among individuals sharing identical genetic mutations. Bruck syndrome (BS), a prime example, is characterized by bone fragility and congenital contractures, although with a pronounced variability among family members. BS arises from recessive biallelic mutations in FKBP10 or PLOD2. FKBP65, the protein encoded by FKBP10, collaborates with the LH2 enzyme (PLOD2) in type I collagen telopeptide lysine hydroxylation, crucial for collagen cross-linking. To identify potential modifier genes and to investigate the mechanistic role of FKBP10 in BS pathogenesis, we established an fkbp10a knockout zebrafish model. Mass-spectrometry analysis in fkbp10a-/- mutants revealed a generally decreased type I collagen lysyl hydroxylation, paralleled by a wide skeletal variability similar to human patients. Ultrastructural examination of the skeleton in severely affected mutants showed enlarged type I collagen fibrils and disturbed elastin layers. Whole-exome sequencing of 7 mildly and 7 severely affected mutant zebrafish siblings, followed by SNP-based linkage analysis, indicated a linked region on chromosome 13, which segregates with phenotypic severity. Transcriptome analysis identified six differentially expressed genes (DEGs) between mildly and severely affected mutants. The convergence of genes within the linked region and DEGs highlighted bmpr1aa as a potential modifier gene, as its reduced expression correlates with increased skeletal severity. In summary, our study provides deeper insights into the role of FKBP10 in BS pathogenesis. Additionally, we identified a pivotal gene that influences phenotypic severity in a zebrafish model of BS. These findings hold promise for novel treatments in the field of bone diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping