Pseudoachondroplasia and multiple epiphyseal dysplasia: Mutation review, molecular interactions, and genotype to phenotype correlations

Briggs, Michael D.; Chapman, Kathryn

doi:10.1002/humu.10066

Cited by 266 publications

(293 citation statements)

References 68 publications

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“…In addition, other skeletal abnormalities, such as pseudoachondrodysplasia (PSACH) or multiple epiphyseal dysplasia (MED) are caused by mutations in cartilage ECM proteins like collagens II, IX, X, and XI, or aggrecan, COMP, and matrilin-3. (26)(27)(28)(29)34,(37)(38)(39)(40)(41)(42)(43) ER stress is thought to constitute the underlying common disease mechanism due to retention of abnormal, improperly folded proteins within the ER. The cells can be rescued after the ER stress-induced unfolded protein response, which arrests the cell cycle, reduces the general protein synthesis, and enhances the production of new chaperones facilitating additional folding processes.…”

Section: Discussionmentioning

confidence: 99%

ER Stress During the Pubertal Growth Spurt Results in Impaired Long-Bone Growth in Chondrocyte-Specific ERp57 Knockout Mice

Linz

Knieper

Gronau

et al. 2015

Journal of Bone and Mineral Research

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Long-bone growth by endochondral ossification is cooperatively accomplished by chondrocyte proliferation, hypertrophic differentiation, and appropriate secretion of collagens, glycoproteins, and proteoglycans into the extracellular matrix (ECM). Before folding and entering the secretory pathway, ECM macromolecules in general are subject to extensive posttranslational modification, orchestrated by chaperone complexes in the endoplasmic reticulum (ER). ERp57 is a member of the protein disulfide isomerase (PDI) family and facilitates correct folding of newly synthesized glycoproteins by rearrangement of native disulfide bonds. Here, we show that ERp57-dependent PDI activity is essential for postnatal skeletal growth, especially during the pubertal growth spurt characterized by intensive matrix deposition. Loss of ERp57 in growth plates of cartilage-specific ERp57 knockout mice (ERp57 KO) results in ER stress, unfolded protein response (UPR), reduced proliferation, and accelerated apoptotic cell death of chondrocytes. Together this results in a delay of long-bone growth with the following characteristics: (1) enlarged growth plates; (2) expanded hypertrophic zones; (3) retarded osteoclast recruitment; (4) delayed remodeling of the proteoglycan-rich matrix; and (5) reduced numbers of bone trabeculae. All the growth plate and bone abnormalities, however, become attenuated after the pubertal growth spurt, when protein synthesis is decelerated and, hence, ERp57 function is less essential.

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Section: Discussionmentioning

confidence: 99%

ER Stress During the Pubertal Growth Spurt Results in Impaired Long-Bone Growth in Chondrocyte-Specific ERp57 Knockout Mice

Linz

Knieper

Gronau

et al. 2015

Journal of Bone and Mineral Research

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“…Three mutations in this part of TSP-5 are associated with PSACH or EDM1 (reviewed in Ref. 19), also suggesting that the linker represents a Ca 2ϩ -binding motif. We further hypothesized that the presence of the Ser-700 polymorphism disrupts this site, but cooperative binding of Ca 2ϩ to adjacent Ca 2ϩ -binding motifs also triggers the conformational change reported by Trp-698.…”

mentioning

confidence: 99%

A Polymorphism in Thrombospondin-1 Associated with Familial Premature Coronary Artery Disease Alters Ca2+ Binding

Hannah

Misenheimer²,

Pranghofer³

et al. 2004

Journal of Biological Chemistry

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A single nucleotide polymorphism that results in substitution at residue 700 of a serine (Ser-700) for an asparagine (Asn-700) in thrombospondin-1 is associated with familial premature coronary artery disease. The polymorphism is located in the first of 13 Ca 2؉ -binding motifs, within a consensus sequence in which Asn-700 likely coordinates Ca 2؉ . Equilibrium dialysis of constructs comprised of the adjoining epidermal growth factor-like module and the Ca 2؉ -binding region (E3Ca) demonstrated that E3Ca Ser-700 binds significantly less Ca 2؉ than E3Ca Asn-700 at low [Ca 2؉ ]. The hypothesis that this difference is due to loss of a binding site in Ser-700 protein was tested with truncations of E3Ca containing four (Tr4), three (Tr3), two (Tr2), or one (Tr1) N-terminal Ca 2؉ -binding motifs. The Ser-700 truncation constructs bound 1 fewer Ca 2؉ than matching Asn-700 constructs and exhibited decreased binding affinities. Intrinsic fluorescence of a tryptophan at residue 698 (Trp-698) in the most N-terminal motif was cooperatively quenched by the addition of Ca 2؉ to Asn-700 Tr2, Tr3, and Tr4 constructs. In Ser-700 constructs, quenching of Trp-698 was incomplete in the Tr2 and Tr3 constructs and complete only in the Tr4 construct. Ca 2؉ -induced quenching of Ser-700 constructs required higher [Ca 2؉ ] and was slower as shown in stopped-flow experiments than quenching of Asn-700 constructs. Such differences were not found with Tb 3؉ , which quenched the fluorescence of Asn-700 and Ser-700 constructs equivalently. Thus, the Ser-700 polymorphism alters a rapidly filled, high affinity Ca 2؉ -binding site in the first Ca 2؉ -binding motif. Slower Ca 2؉ binding to adjoining motifs partly compensates for the change.

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“…Mutations in either COMP or matrilin 3 are associated with human diseases that affect skeletal development (15)(16)(17), but development proceeds normally in both COMP and matrilin 3 single-deficient mice, without any pronounced skeletal abnormalities (18,19). To elucidate the role of COMP and matrilin 3 in osteogenesis and to investigate putative compensatory roles of the two adaptor proteins, we generated mice deficient in both molecules.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in both matrilin 3 and COMP have been linked to multiple epiphyseal dysplasia in humans, the pathogenesis of which includes both intracellular and extracellular alterations (15)(16)(17). Despite the large number of studies on matrilins and COMP, their roles in the function, assembly, and remodeling of the cartilage extracellular matrix are not fully understood.…”

mentioning

confidence: 99%

Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double‐deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation

Groma¹,

Xin²,

Grskovic³

et al. 2012

Arthritis & Rheumatism

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Objective. Cartilage oligomeric matrix protein (COMP) and matrilin 3 are extracellular matrix proteins that are abundant in cartilage. As adaptor molecules, both proteins bridge and stabilize macromolecular networks consisting of fibrillar collagens and proteoglycans. Mutations in the genes coding for COMP and matrilin 3 have been linked to human chondrodysplasias, while in mice, deficiency in COMP or matrilin 3 does not cause any pronounced skeletal abnormalities. Given the similar functions of COMP and matrilin 3 in the assembly and stabilization of the extracellular matrix, our aim was to determine whether these proteins could functionally compensate for each other.Methods. To assess this putative redundancy of COMP and matrilin 3, we generated COMP/matrilin 3 double-deficient mice and performed an in-depth analysis of their skeletal development.Results. At the newborn stage, the overall skeletal morphology of the double mutants was normal, but at 1 month of age, the long bones were shortened and the total body length reduced. Peripheral quantitative computed tomography revealed increased metaphyseal trabecular bone mineral density in the femora. Moreover, the degradation of aggrecan in the cartilage remnants in the metaphyseal trabecular bone was delayed, paralleled by increased deposition of tissue inhibitor of metalloproteinases 3 (TIMP-3). The structure and morphology of the growth plate were grossly normal, but in the center, focal closures were observed, a phenotype very similar to that described in matrix metalloproteinase 13 (MMP-13)-deficient mice.Conclusion. We propose that a lack of COMP and matrilin 3 leads to increased deposition of TIMP-3, which causes partial inactivation of MMPs, including MMP-13, a mechanism that would explain the similarities in phenotype between COMP/matrilin 3 doubledeficient and MMP-13-deficient mice.The 2 major components of the cartilage extracellular matrix are the fibrillar collagens and the large hyaluronan-binding proteoglycan aggrecan. A variety of different proteins, including cartilage oligomeric matrix protein (COMP) and matrilin 3, modulate the assembly and structure of the extracellular matrix, generating complex functional networks. Matrilins are noncollagenous oligomeric extracellular matrix proteins with similar domain structure and function. Matrilin 1 and matrilin 3 are found almost exclusively in cartilage, while matrilin 2 and matrilin 4 have a broader tissue distribution. Subunits of matrilins 1 and 4 mainly form homotrimers, whereas subunits of matrilins 2 and 3 are found in homotetramers (1,2). In addition, heterotrimers consisting of matrilin 1 and matrilin 3 subunits can form. Matrilins function as adaptor proteins in the extracellular matrix and connect collagen fibrils with each other and with aggrecan (2). Via their von Willebrand type A-like domain, matrilins interact with several other matrix components, including COMP (3),

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Pseudoachondroplasia and multiple epiphyseal dysplasia: Mutation review, molecular interactions, and genotype to phenotype correlations

Cited by 266 publications

References 68 publications

ER Stress During the Pubertal Growth Spurt Results in Impaired Long-Bone Growth in Chondrocyte-Specific ERp57 Knockout Mice

ER Stress During the Pubertal Growth Spurt Results in Impaired Long-Bone Growth in Chondrocyte-Specific ERp57 Knockout Mice

A Polymorphism in Thrombospondin-1 Associated with Familial Premature Coronary Artery Disease Alters Ca2+ Binding

Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double‐deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation

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