Cartilage hair hypoplasia in infancy: A misleading chondrodysplasia

“…The variable phenotype exhibited by the BCS embryos is common in the ribosomopathies [48][49][50], and is not unexpected on a mixed CD1/ C129/C57BL/6 background. We are currently establishing a congenic C57BL/6 line to address genetic background effects on phenotypic variability.…”

Section: Discussionmentioning

confidence: 92%

Growth arrest in the ribosomopathy, Bowen–Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression

Armistead

Patel

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Bowen-Conradi syndrome (BCS) is a ribosomopathy characterized by severe developmental delay and growth failure that typically leads to death by one year of age. It is caused by a c.257A>G, p.D86G substitution in the ribosomal biogenesis protein, Essential for Mitotic Growth 1 (EMG1). We generated a knock-in of the D86G substitution in mice to characterize the effects of EMG1 deficiency, particularly in the brain, where EMG1 expression is high. Embryos homozygous for the mutation in Emg1 were small for gestational age with neural tube defects, and died between embryonic days 8.5 and 12.5. These embryos exhibited dramatically reduced cell proliferation, which we also detected in autopsy brain tissue and bone marrow of BCS patients, consistent with a requirement for high levels of EMG1 in tissues with rapid cell proliferation. In fibroblasts derived from the BCS mouse embryos, we detected a high proportion of binucleated cells, indicating that a mitotic defect underlies the growth arrest in BCS. These studies add to growing evidence of a link between ribosome biogenesis, mitotic progression, and brain development that is currently unexplored.

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“…It has been reported that some CHH patients have abnormal ossification . To study the effect of rmrp mutation on bone formation in zebrafish, we used live‐ staining with Alizarin Red and the transgenic line Tg(osterix:EGFP) , which labels osteoblasts to examine the ossification of the skulls.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that some CHH patients have abnormal ossification. (1,35,36) To study the effect of rmrp mutation on bone formation in zebrafish, we used live-staining with Alizarin Red and the transgenic line Tg(osterix:EGFP), which labels osteoblasts to examine the ossification of the skulls. From 6 dpf to 9 dpf, confocal microscopy revealed that both intramembranous bone and endochondral bone were gradually ossified in the skulls of WT zebrafish; however, in rmrp mutants, the ossification of intramembranous bone in opercle, branchiostegal rays, and dentary was delayed (Fig.…”

Section: Rmrp Is Required For the Timely Bone Ossificationmentioning

confidence: 99%

Rmrp Mutation Disrupts Chondrogenesis and Bone Ossification in Zebrafish Model of Cartilage-Hair Hypoplasia via Enhanced Wnt/β-Catenin Signaling

Sun

Zhang

Liu

et al. 2019

Journal of Bone and Mineral Research

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Cartilage‐hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by bone dysplasia and many other highly variable features. The gene responsible for CHH is the RNA component of the mitochondrial RNA‐processing endoribonuclease (RMRP) gene. Currently, the pathogenesis of osteochondrodysplasia and extraskeletal manifestations in CHH patients remains incompletely understood; in addition, there are no viable animal models for CHH. We generated an rmrp KO zebrafish model to study the developmental mechanisms of CHH. We found that rmrp is required for the patterning and shaping of pharyngeal arches. Rmrp mutation inhibits the intramembranous ossification of skull bones and promotes vertebrae ossification. The abnormalities of endochondral bone ossification are variable, depending on the degree of dysregulated chondrogenesis. Moreover, rmrp mutation inhibits cell proliferation and promotes apoptosis through dysregulating the expressions of cell‐cycle‐ and apoptosis‐related genes. We also demonstrate that rmrp mutation upregulates canonical Wnt/β‐catenin signaling; the pharmacological inhibition of Wnt/β‐catenin could partially alleviate the chondrodysplasia and increased vertebrae mineralization in rmrp mutants. Our study, by establishing a novel zebrafish model for CHH, partially reveals the underlying mechanism of CHH, hence deepening our understanding of the role of rmrp in skeleton development.

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Cartilage hair hypoplasia in infancy: A misleading chondrodysplasia

Cited by 21 publications

References 12 publications

Short-limbed dwarfism with bowing, combined immune deficiency, and late onset aplastic anaemia caused by novel mutations in the RMPR gene

Short-limbed dwarfism with bowing, combined immune deficiency, and late onset aplastic anaemia caused by novel mutations in the RMPR gene

Growth arrest in the ribosomopathy, Bowen–Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression

Rmrp Mutation Disrupts Chondrogenesis and Bone Ossification in Zebrafish Model of Cartilage-Hair Hypoplasia via Enhanced Wnt/β-Catenin Signaling

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