Molecular Study of a Hoxa2 Gain-of-Function in Chondrogenesis: A Model of Idiopathic Proportionate Short Stature

Deprez, Pierre; Nichane, Miloud G; Lengelé, Benoît; Rezsöhazy, René; Behets, Catherine

doi:10.3390/ijms141020386

Cited by 7 publications

(4 citation statements)

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“…For example, BMPR1A that ranked second overall is essential for embryogenesis [ 57 ], including skeletogenesis, and postnatal bone homeostasis [ 58 ]. Expression of BMPR1A was shown to be downregulated in a mouse model for human idiopathic proportionate short stature [ 59 ]. It is also involved in the regulation of adipogenesis and variants of BMPR1A are associated with human obesity [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Combined GWAS and ‘guilt by association’-based prioritization analysis identifies functional candidate genes for body size in sheep

et al. 2017

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BackgroundBody size in sheep is an important indicator of productivity, growth and health as well as of environmental adaptation. It is a composite quantitative trait that has been studied with high-throughput genomic methods, i.e. genome-wide association studies (GWAS) in various mammalian species. Several genomic markers have been associated with body size traits and genes have been identified as causative candidates in humans, dog and cattle. A limited number of related GWAS have been performed in various sheep breeds and have identified genomic regions and candidate genes that partly account for body size variability. Here, we conducted a GWAS in Frizarta dairy sheep with phenotypic data from 10 body size measurements and genotypic data (from Illumina ovineSNP50 BeadChip) for 459 ewes.ResultsThe 10 body size measurements were subjected to principal component analysis and three independent principal components (PC) were constructed, interpretable as width, height and length dimensions, respectively. The GWAS performed for each PC identified 11 significant SNPs, at the chromosome level, one on each of the chromosomes 3, 8, 9, 10, 11, 12, 19, 20, 23 and two on chromosome 25. Nine out of the 11 SNPs were located on previously identified quantitative trait loci for sheep meat, production or reproduction. One hundred and ninety-seven positional candidate genes within a 1-Mb distance from each significant SNP were found. A guilt-by-association-based (GBA) prioritization analysis (PA) was performed to identify the most plausible functional candidate genes. GBA-based PA identified 39 genes that were significantly associated with gene networks relevant to body size traits. Prioritized genes were identified in the vicinity of all significant SNPs except for those on chromosomes 10 and 12. The top five ranking genes were TP53, BMPR1A, PIK3R5, RPL26 and PRKDC.ConclusionsThe results of this GWAS provide evidence for 39 causative candidate genes across nine chromosomal regions for body size traits, some of which are novel and some are previously identified candidates from other studies (e.g. TP53, NTN1 and ZNF521). GBA-based PA has proved to be a useful tool to identify genes with increased biological relevance but it is subjected to certain limitations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12711-017-0316-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Combined GWAS and ‘guilt by association’-based prioritization analysis identifies functional candidate genes for body size in sheep

et al. 2017

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“…CD5 has been previously described as being overexpressed in the synovial fluid of patients with advanced OA but has not been described previously in subchondral bone. Finally, overexpression of hypermethylated HOXA2 in murine models results in chondrodysplasia and delayed cartilage maturation ; similarly, its expression can delay endochondral ossification .…”

Section: Discussionmentioning

confidence: 99%

Genome‐Wide DNA Methylation Study Identifies Significant Epigenomic Changes in Osteoarthritic Subchondral Bone and Similarity to Overlying Cartilage

Jeffries

Donica

Baker

et al. 2016

Arthritis & Rheumatology

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Objective To perform a genome-wide DNA methylation study to identify differential DNA methylation patterns in subchondral bone underlying eroded and intact cartilage from patients with hip osteoarthritis (OA) and to compare these with DNA methylation patterns in overlying cartilage. Methods Genome-wide DNA methylation profiling using Illumina HumanMethylation 450 arrays was performed on eroded and intact cartilage and subchondral bone from within the same joint of 12 patients undergoing hip arthroplasty. Genes with differentially methylated CpG sites were analyzed to identify shared pathways, upstream regulators, and overrepresented gene ontologies, and these patterns were compared with those of the overlying cartilage. Histopathology was graded by modified Mankin score and assessed for correlation with DNA methylation. Results We identified 7,316 differentially methylated CpG sites in subchondral bone underlying eroded cartilage, most of which (~75%) were hypomethylated, and 1,397 sites in overlying eroded cartilage, 126 of which were shared. Samples clustered into 3 groups with distinct histopathologic scores. We observed differential DNA methylation of genes including the RNA interference–processing gene AGO2, the growth factor TGFB3, the OA suppressor NFATC1, and the epigenetic effector HDAC4. Among known susceptibility genes in OA, 32 were differentially methylated in subchondral bone, 8 were differentially methylated in cartilage, and 5 were shared. Upstream regulator analysis using differentially methylated genes in OA subchondral bone showed a strong transforming growth factor β1 signature (P = 1 × 10−40) and a tumor necrosis factor family signature (P = 3.2 × 10−28), among others. Conclusion Our data suggest the presence of an epigenetic phenotype associated with eroded OA subchondral bone that is similar to that of overlying eroded OA cartilage.

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“…At days 28 and 56, HOXA2 , HOXA3 , and HOXA4 were in the top up-regulated genes, with HOXA4 having the largest fold change. Interestingly, gain-of-function mutations or overexpression of HOXA2 , HOXA3 , and HOXA4 impair chondrogenesis, limit skeletal development, decrease endochondral ossification regulators, and delay mineralization in animal models ( Creuzet et al, 2002 ; Deprez et al, 2013 ; Kanzler et al, 1998 ; Li and Cao, 2006 ; Massip et al, 2007 ; Seifert et al, 2015 ). HOXA5 was also highly up-regulated at both days 28 and 56, and mutations in this gene showed disordered patterning of limb bud development ( Pineault and Wellik, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

Dicks

Maksaev

Harissa

et al. 2023

eLife

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Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype. There were no differences in overall cartilaginous matrix production, but the V620I mutation resulted in reduced mechanical properties of cartilage matrix later in chondrogenesis. mRNA sequencing revealed that both mutations upregulated several anterior HOX genes and downregulated antioxidant genes CAT and GSTA1 throughout chondrogenesis. BMP4 treatment upregulated several essential hypertrophic genes in WT chondrocytes; however, this hypertrophic maturation response was inhibited in mutant chondrocytes. These results indicate that the TRPV4 mutations alter BMP signaling in chondrocytes and prevent proper chondrocyte hypertrophy, as a potential mechanism for dysfunctional skeletal development. Our findings provide potential therapeutic targets for developing treatments for TRPV4-mediated skeletal dysplasias.

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Molecular Study of a Hoxa2 Gain-of-Function in Chondrogenesis: A Model of Idiopathic Proportionate Short Stature

Cited by 7 publications

References 64 publications

Combined GWAS and ‘guilt by association’-based prioritization analysis identifies functional candidate genes for body size in sheep

Combined GWAS and ‘guilt by association’-based prioritization analysis identifies functional candidate genes for body size in sheep

Genome‐Wide DNA Methylation Study Identifies Significant Epigenomic Changes in Osteoarthritic Subchondral Bone and Similarity to Overlying Cartilage

Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

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