Metaphyseal chondrodysplasia, Schmid type. A defect of ultrastructural metabolism

Wasylenko, M J; Wedge, J. H.; Houston, C S

doi:10.2106/00004623-198062040-00023

Cited by 17 publications

(3 citation statements)

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“…A very recent study showed that nonsense mutations leads to the complete degradation of mutant collagen X mRNA in cartilage in SMCD (Bateman et al, 2003). Interestingly, SMCD patients also have an altered zone of hypertrophy (Wasylenko et al, 1980;Lachman et al, 1988;Nielsen et al, 2000). However, it appears that chondrocyte hypertrophy by itself, at least in mice, does not require type X collagen (Rosati et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte–specific expression in vivo

Zheng

Zhou

Morello

et al. 2003

The Journal of Cell Biology

286

329

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The α1(X) collagen gene (Col10a1) is the only known hypertrophic chondrocyte–specific molecular marker. Until recently, few transcriptional factors specifying its tissue-specific expression have been identified. We show here that a 4-kb murine Col10a1 promoter can drive β-galactosidase expression in lower hypertrophic chondrocytes in transgenic mice. Comparative genomic analysis revealed multiple Runx2 (Runt domain transcription factor) binding sites within the proximal human, mouse, and chick Col10a1 promoters. In vitro transfection studies and chromatin immunoprecipitation analysis using hypertrophic MCT cells showed that Runx2 contributes to the transactivation of this promoter via its conserved Runx2 binding sites. When the 4-kb Col10a1 promoter transgene was bred onto a Runx2 +/− background, the reporter was expressed at lower levels. Moreover, decreased Col10a1 expression and altered chondrocyte hypertrophy was also observed in Runx2 heterozygote mice, whereas Col10a1 was barely detectable in Runx2-null mice. Together, these data suggest that Col10a1 is a direct transcriptional target of Runx2 during chondrogenesis.

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Section: Discussionmentioning

confidence: 99%

Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte–specific expression in vivo

Zheng

Zhou

Morello

et al. 2003

The Journal of Cell Biology

286

329

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“…ER dilation was observed in the chondrocytes of a patient with MCDS (Wasylenko et al, 1980) and recent evidence indicates that the impact of ER stress is a major cause of the MCDS phenotype. Collagen X misfolding induces ER stress and the UPR directly in transfected cells .…”

Section: Mutated Er Client Proteins: Ecm Gene Mutations In Skeletal Dmentioning

confidence: 88%

“…Metaphyseal chondrodysplasia, type Schmid (MCDS) (MIM #156500); patients develop disproportionate dwarfism after birth (Lachman et al, 1988;Makitie et al, 2005) An unidentified mutation that caused MCDS showed ER dilation (Wasylenko et al, 1980) Mice carrying mutations p.P620fsX672 (13del) , p.P620fsX621 (Cdel) (Ho et al, 2007) or p.N617K (Rajpar et al, 2009) Multiple epiphyseal dysplasias (EDM) and pseudoachondroplasia (PSACH) (MIM# 177170), which can be thought of as a much more severe form of EDM1 (Briggs and Chapman, 2002) EDM1: p.469insD (Delot et al, 1998;Delot et al, 1999) PSACH: p.G427E, p.469insDD (Delot et al, 1998;Delot et al, 1999), p.469delD, p.G427E (Hecht et al, 1998), p.D346N (Maddox et al, 1997, p.G465S (Cotterill et al, 2005) p.T583M (Pirog-Garcia et al, 2007); homozygous mutant mice display a more severe dwarfism than the heterozygous, observed significantly at 9 weeks of age. Increased expression of BiP, phosphorylated eIF2 and CHOP; ATF6 cleavage MATN3 (matrilin-3)…”

Section: Mutated Er Client Proteins: Ecm Gene Mutations In Skeletal Dmentioning

confidence: 99%

In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences

Tsang

Chan

Bateman

et al. 2010

Journal of Cell Science

116

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SummaryDisturbances to the balance of protein synthesis, folding and secretion in the endoplasmic reticulum (ER) induce stress and thereby the ER stress signaling (ERSS) response, which alleviates this stress. In this Commentary, we review the emerging idea that ER stress caused by abnormal physiological conditions and/or mutations in genes that encode client proteins of the ER is a key factor underlying different developmental processes and the pathology of diverse diseases, including diabetes, neurodegeneration and skeletal dysplasias. Recent studies in mouse models indicate that the effect of ERSS in vivo and the nature of the cellular strategies induced to ameliorate pathological ER stress are crucial factors in determining cell fate and clinical disease features. Importantly, ERSS can affect cellular proliferation and the differentiation program; cells that survive the stress can become 'reprogrammed' or dysfunctional. These cellautonomous adaptation strategies can generate a spectrum of context-dependent cellular consequences, ranging from recovery to death. Secondary effects can include altered cell-extracellular-matrix interactions and non-cell-autonomous alteration of paracrine signaling, which contribute to the final phenotypic outcome. Recent reports showing that ER stress can be alleviated by chemical compounds suggest the potential for novel therapeutic approaches. (1) Physiological ER stress during development is mild and controllable. The cell can recover from and/or adapt to the protein-folding stress; it can also differentiate into a specialized cell type in a manner that depends on components of ERSS and appropriate developmental signals. (2) In severe pathological ER stress, ERSS is initially an adaptive response, but, if stress remains unresolved, perhaps because of continuous and/or cyclical expression of mutant protein, it can lead to interference with developmental signals and disruption of cellular gene expression patterns. The cell can then display altered proliferation and differentiation status, and become dysfunctional. (3) Under conditions of extreme stress, an apoptotic signal is triggered and becomes dominant, leading to cell death. This can occur through excessive production of reactive oxygen species (ROS) caused by enhanced protein-folding activity, which relates to levels of CHOP, GADD34 and ERO1 expression. Journal of Cell Science Attenuation of translationOne of the early responses to ER stress is the modulation of translation, a highly conserved adaptation mechanism (Yamasaki and Anderson, 2008). Phosphorylation of eukaryotic initiation factor 2 (eIF2) by PERK reduces protein translation and shifts the translation machinery to favor alternative modes of initiation, including selective translation of activating transcription factor 4 (ATF4) . Phosphorylated eIF2 also activates the conversion of microtubule-associated protein 1 light chain 3 (LC3-I), an essential protein for autophagy, to LC3-II and hence promotes autophagosome formation Kouroku et al., 2007), as well as t...

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Metaphyseal anadysplasia: A metaphyseal dysplasia of early onset with radiological regression and benign course

Maroteaux

Verloes²,

Stănescu

et al. 1991

Am. J. Med. Genet.

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We report on 4 boys (including 2 maternally related first cousins) with a metaphyseal dysplasia of early onset and regressive evolution. Diagnosis is possible in the first months. Distal metaphyses of long bones are very irregular. Femoral necks seem hypoplastic and the edges of the metaphyses are almost vertical; femoral shaft is bowed. Those anomalies disappear after 2 years. The main manifestations are slight shortness and a light varus deformity of the lower limbs. Stature is not affected. The upper tibial growth cartilage, studied in one case, showed wide proliferative and hypertrophic zones with an unusual appearance of the last hypertrophic cells and an abnormal zone of cartilage calcification and resorption. The name "metaphyseal anadysplasia" is suggested for this early and regressive disorder. We are aware of other forms of regressive metaphyseal dysplasia which deserve further delineation. Therefore infants whose radiological changes of metaphyseal dysplasia do not fall into one of the well-defined types should be followed and prediction of the adult height should not be made on the basis of the findings on the initial examination.

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Metaphyseal chondrodysplasia, Schmid type. A defect of ultrastructural metabolism

Cited by 17 publications

References 0 publications

Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte–specific expression in vivo

Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte–specific expression in vivo

In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences

Metaphyseal anadysplasia: A metaphyseal dysplasia of early onset with radiological regression and benign course

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