Molecular structure of Fgfbp1 protein and its regulation of zebrafish cartilage development and homeostasis: Implications for Wnt signaling and ECM stability

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 142340 - 142340

Published: March 1, 2025

Language: Английский

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Extracellular and intracellular effects of bioactive glass nanoparticles on osteogenic differentiation of bone marrow mesenchymal stem cells and bone regeneration in zebrafish osteoporosis model

Acta Biomaterialia, Journal Year: 2023, Volume and Issue: 174, P. 412 - 427

Published: Nov. 30, 2023

Language: Английский

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Functional Validation of Osteoporosis Genetic Findings Using Small Fish Models

Genes, Journal Year: 2022, Volume and Issue: 13(2), P. 279 - 279

Published: Jan. 30, 2022

The advancement of human genomics has revolutionized our understanding the genetic architecture many skeletal diseases, including osteoporosis. However, interpreting results from association studies remains a challenge, since index variants often reside in non-coding regions genome and do not possess an obvious regulatory function. To bridge gap between causality, systematic functional investigation is necessary, such as one offered by animal models. These models enable us to identify causal mechanisms, clarify underlying biology, apply interventions. Over past several decades, small teleost fishes, mostly zebrafish medaka, have emerged powerful systems for modeling genetics diseases. Due their amenability intervention highly conserved physiological features, fish become indispensable genomic studies. goal this review summarize evidence supporting utility Zebrafish (

Language: Английский

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Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: July 4, 2023

Abstract Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform genome-wide association meta-analysis ( n ~ 43,800) SK-BMD, identifying 59 loci, collectively explaining 12.5% variance. Association signals cluster within gene-sets involved development and osteoporosis. Among four novel loci ZIC1 , PRKAR1A AZIN1/ATP6V1C1 GLRX3 ), there are factors implicated ossification as we show, inherent craniosynostosis processes. Functional follow-up zebrafish confirms importance on cranial suture patterning. Likewise, observe abnormal initiation that culminates ectopic sutures reduced BMD mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric growth and, conversely, elevated BMD. In light this evidence linking SK-BMD craniofacial abnormalities, our study new insight into pathophysiology, diagnosis treatment diseases.

Language: Английский

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

Published: Jan. 2, 2025

Heritable Fragile Bone Disorders (FBDs) encompass a spectrum of conditions, from widespread multifactorial to rare monogenic diseases, all characterized by an elevated risk fractures. The process validating causative genes and elucidating their pathogenic mechanisms remains daunting resource-intensive task. In this study, we evaluated the feasibility semi-high throughput zebrafish screening platform for rapid validation in vivo functional testing candidate disease-causing wide range heritable FBDs. Six associated with severe recessive forms Osteogenesis Imperfecta (OI) four bone mineral density (BMD), key osteoporosis indicator, identified through genome-wide association studies (GWAS) were selected. crispant approach, based on CRISPR/Cas9 technology, was used phenotype directly F0 mosaic founder zebrafish. Next-Generation Sequencing (NGS) analysis revealed mean indel efficiency 88% across ten different crispants, indicating high proportion knock-out alleles thus resembling stable models. We applied multiple techniques evaluate skeletal characteristics at 7, 14 90 days post-fertilization (dpf), including microscopy osteoblast reporter visualization mineralization Alizarin Red S staining, microCT quantitative analysis. While larval crispants exhibited variable differences osteoblast-positive mineralized surface areas, adult-stage displayed more pronounced consistent phenotypes. Notably, developed malformed neural haemal arches, majority presenting vertebral fractures fusions, some showing significant alterations volume density. addition, aldh7a1 mbtps2 experienced increased mortality due deformities. RT-qPCR differentiation formation markers stages indicated differential expression osteogenic bglap col1a1a substantial portion hinting utility as biomarkers FBD screening. summary, our findings demonstrate that offers viable efficient strategy assessment genes. advocate novel comprehensive approach integrates various evaluates distinct molecular profiles developmental adult stages. This methodology has potential provide new insights into role these biology.

Language: Английский

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

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 16, 2025

Heritable fragile bone disorders (FBDs), ranging from multifactorial to rare monogenic conditions, are characterized by an elevated fracture risk. Validating causative genes and understanding their mechanisms remain challenging. We assessed a semi-high throughput zebrafish screening platform for rapid in vivo functional testing of candidate FBD genes. Six linked severe recessive osteogenesis imperfecta (OI) four associated with mineral density (BMD) genome-wide association studies were analyzed using CRISPR/Cas9-based crispant F0 mosaic founder zebrafish. Next-generation sequencing confirmed high indel efficiency (mean 88%), mimicking stable knock-out models. Skeletal phenotyping at 7, 14, 90 days post-fertilization (dpf) microscopy, Alizarin Red S staining, microCT was performed. Larval crispants showed variable osteoblast mineralization phenotypes, while adult displayed consistent skeletal defects, including malformed neural haemal arches, vertebral fractures fusions, altered volume density. In addition, aldh7a1 mbtps2 experienced increased mortality due deformities. RT-qPCR revealed differential expression osteogenic markers bglap col1a1a , highlighting biomarker potential. Our results establish as robust tool gene validation, combining molecular analyses across developmental stages uncover novel insights into functions biology.

Language: Английский

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Multi-ancestry whole genome sequencing analysis of lean body mass

Genome biology, Journal Year: 2025, Volume and Issue: 26(1)

Published: April 28, 2025

Lean body mass is a crucial physiological component of composition. Although lean has high heritability, studies evaluating the genetic determinants (LM) have to date been limited largely genome-wide association (GWAS) and common variants. Using whole genome sequencing (WGS)-based studies, we aimed discover novel variants associated with LM in population-based cohorts multiple ancestries. We describe largest WGS-based meta-analysis date, encompassing 10,729 WGS samples from six TOPMed Louisiana Osteoporosis Study (LOS) cohort, measured dual-energy X-ray absorptiometry. identify seven loci significantly not reported by previous GWAS. partially replicate these associations UK Biobank samples. In rare variant analysis, one protein-coding gene, DMAC1, both whole-body appendicular females, long non-coding RNA gene linked males. Both genes exhibit notably expression levels skeletal muscle tissue. investigate functional roles two lean-mass-related genes, EMP2 SSUH2, animal models. deficiency Drosophila leads reduced mobility without altering tissue or fat morphology, whereas an SSUH2 mutation zebrafish stimulates fiber growth. Our comprehensive large-scale investigations, reveals genomic traits, shedding new insights into pathways influencing metabolism regulation.

Language: Английский

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Further delineation of defects in MRPS2 causing human OXPHOS deficiency and early developmental abnormalities in zebrafish

European Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: May 13, 2025

Abstract Mitochondrial ribosomal protein-small 2 ( MRPS2 ) encodes a vital structural protein essential for assembling mitoribosomal small subunit and thus mitochondrial translation. Any defect in translation impacts OXPHOS activity cellular respiration. Defects have been implicated recently four families with combined oxidative phosphorylation deficiency-36 (MIM# 617950). We herein describe two individuals from unrelated variable phenotypes of acute onset severe metabolic decompensation symptomatic hypoglycemia. Exome sequencing identified bi-allelic variants (NM_016034.5) the affected individuals: P1: c.490 G > A p.(Glu164Lys); P2: c.413 p.(Arg138His). Further evaluation variant p.(Glu164Lys) patient-derived skin fibroblasts revealed decreased expression transcript levels along complex I IV proteins. Proteomics analysis proteins increased large Also, reduced enzyme activities, respiration (OCR), altered morphology on confocal imaging were observed. Additionally, mrps2 knockout zebrafish larvae demonstrated an abnormal developmental phenotype Complex activity. With these findings, we identify additional , illustrating clinical spectrum validate pathogenicity defects through in-vitro in-vivo assays.

Language: Английский

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Genetically engineered zebrafish as models of skeletal development and regeneration

Bone, Journal Year: 2022, Volume and Issue: 167, P. 116611 - 116611

Published: Nov. 14, 2022

Language: Английский

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Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics

Molecular Aspects of Medicine, Journal Year: 2022, Volume and Issue: 91, P. 101153 - 101153

Published: Nov. 18, 2022

Precision medicine strives for highly individualized treatments disease under the notion that each individual's unique genetic makeup and environmental exposures imprints upon them not only a disposition to illness, but also an optimal therapeutic approach. In realm of rare disorders, predisposition is often predominant mechanism driving presentation. For such, mostly, monogenic causal gene phenotype association likely. As result, it becomes important query patient's genome presence pathogenic variations are likely cause disease. Determining whether variant or critical these analyses can be challenging, as many disease-causing variants novel and, ergo, have no available functional data help categorize them. This problem exacerbated by need rapid evaluation pathogenicity, since diseases present in young children who will experience increased morbidity mortality without diagnosis therapeutics. Here, we discuss utility animal models, with focus mainly on C. elegans, contrast tissue culture silico approaches, emphasis how systems used determining pathogenicity uncertain significance then screen

Language: Английский

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