SERPINF1 gene variants causing late-onset progressive deforming osteogenesis imperfecta – A study of 18 patients from India

Madhuri, Vrisha; Selina, Agnes; Kandagaddala, Madhavi; Kumar, Vignesh; Abraham, Sunil; Danda, Sumita

doi:10.1016/j.bonr.2023.101690

Cited by 3 publications

(2 citation statements)

References 24 publications

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“…Interestingly, during these early stages, the majority of the crispants do not exhibit consistent skeletal abnormalities. Although this could be partially explained by the above-discussed variability of the phenotypic outcomes we measured, also human OI subjects with these severe conditions, often experience disease onset during infancy only, with progressive worsening of the skeletal phenotype (Selina et al ., 2023).…”

Section: Discussionmentioning

confidence: 99%

Crispant analysis in zebrafish as a tool for rapid functional screening of disease-causing genes for bone fragility

Debaenst,

Jarayseh,

de Saffel

et al. 2024

Preprint

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Heritable Fragile Bone Disorders (FBDs) encompass a spectrum of conditions, from widespread multifactorial to rare monogenic diseases, all characterized by an elevated risk of fractures. The process of validating causative genes and elucidating their pathogenic mechanisms remains a daunting and resource-intensive task. In this study, we evaluated the feasibility of a semi-high throughput zebrafish screening platform for rapid validation andin vivofunctional testing and validation of candidate disease-causing genes for a wide range of heritable FBDs. Six genes associated with severe recessive forms of Osteogenesis Imperfecta (OI) and four genes associated with BMD, a key osteoporosis indicator, identified through genome-wide association studies (GWAS) were selected. The crispant screening approach, based on CRISPR/Cas9 technology, was used to phenotype directly in F0 mosaic founder zebrafish. Next-Generation Sequencing (NGS) analysis revealed a mean indel efficiency of 88% across ten different crispants, indicating a high proportion of knock-out alleles and thus resembling stable knock-out models. We applied multiple techniques to evaluate skeletal characteristics at 7, 14 and 90 days post-fertilization (dpf), including microscopy for osteoblast reporter visualization and mineralization by Alizarin Red S staining, and microCT for quantitative skeletal analysis. While larval crispants exhibited variable differences in osteoblast-positive and mineralized surface areas, adult-stage crispants displayed more pronounced and consistent skeletal phenotypes. Notably, all crispants developed malformed neural and haemal arches, with a majority presenting vertebral fractures and fusions, and some showing significant alterations in vertebral bone volume and density. In addition,aldh7a1andmbtps2crispants experienced increased mortality due to severe skeletal deformities. RT-qPCR analysis of osteoblast differentiation and bone formation markers at larval stages indicated differential expression of osteogenic markersbglapandcol1a1ain a substantial portion of the crispants, hinting at their utility as biomarkers for FBD crispant screening. In summary, our findings demonstrate that crispant screening in zebrafish offers a viable and efficient strategy for the functional assessment of FBD genes. We advocate for a comprehensive approach that integrates various techniques and evaluates distinct skeletal and molecular profiles across different developmental and adult stages. This methodology has the potential to provide new insights into the role of these genes in skeletal biology.

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Section: Discussionmentioning

confidence: 99%

Crispant analysis in zebrafish as a tool for rapid functional screening of disease-causing genes for bone fragility

Debaenst,

Jarayseh,

de Saffel

et al. 2024

Preprint

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“…Recessive forms of osteogenesis imperfecta (OI) are rare in the Western population (10%-15%) 1 but higher in the Middle East and South Asia (30%-40%) 2,3 of all OI cases. Cyclic AMP responsive element-binding protein 3–like 1 ( CREB3L1) gene mutations cause a rare recessive type of OI XVI and encodes old astrocyte specifially induced substances (OASIS), an endoplasmic reticulum (ER) stress transducer, and a basic leucine zipper transcription factor 4 .…”

mentioning

confidence: 99%

Pamidronate Response in a Novel Biallelic CREB3L1 Gene Mutation–Associated Osteogenesis Imperfecta

Selina,

Kandagaddala,

Madhuri

2024

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Case: We report a 15-year-old adolescent boy being followed up for 6 years with osteogenesis imperfecta (OI). Genetic testing of this child revealed a novel missense variant c.925C>T p.Arg309Cys in the CREB3L1 gene. Treatment with regular pamidronate therapy showed increased bone mineral density and a reduced fracture rate. His lower limb rush rodding improved his mobility. His withdrawal from bisphosphonate therapy worsened his mobility status but started improving after he restarted treatment, suggesting a response to pamidronate therapy. Conclusion: We report a novel biallelic missense variant c.925C>T, p.Arg309Cys, in the CREB3L1 gene causing OI, which responded to bisphosphonate therapy and corrective surgery.

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Skeletal and Non-skeletal Phenotypes in Children with Osteogenesis Imperfecta

Marulanda,

Retrouvey,

Rauch

2024

Calcif Tissue Int

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SERPINF1 gene variants causing late-onset progressive deforming osteogenesis imperfecta – A study of 18 patients from India

Cited by 3 publications

References 24 publications

Crispant analysis in zebrafish as a tool for rapid functional screening of disease-causing genes for bone fragility

Crispant analysis in zebrafish as a tool for rapid functional screening of disease-causing genes for bone fragility

Pamidronate Response in a Novel Biallelic CREB3L1 Gene Mutation–Associated Osteogenesis Imperfecta

Skeletal and Non-skeletal Phenotypes in Children with Osteogenesis Imperfecta

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