Abnormal Type II Collagen in the Spondyloepiphyseal Dysplasias

Murray, Louann W.; Rimoin, David L.

doi:10.1159/000157111

Cited by 52 publications

(38 citation statements)

References 12 publications

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“…The present study establishes the importance of intracellular vesicle traffic in mammalian postnatal bone formation, a highly organized process involving chondrocyte proliferation, differentiation, apoptosis, and calcification (1,2). In principle, transport defects could affect endochondral bone formation at a number of levels, including the synthesis, processing, secretion, or uptake of growth factors, extracellular matrix, and matrix-remodeling proteases (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Such factors also spatially regulate chondrocyte proliferation and apoptosis within the growth plate, consistent with reductions in BrdU and caspase 3-positive cells and growth plate histology in Dym-mutant mice.…”

Section: Discussionsupporting

confidence: 66%

“…Inherited defects in bone formation, or osteochondrodysplasias, are responsible for more than 200 clinically distinct diseases that occur with a cumulative incidence exceeding 1 in 10,000 live births (3,4) caused by mutations in processes critical for osseous bone formation and maintenance. These include growth factor signaling (5), extracellular matrix synthesis (6)(7)(8)(9)(10)(11)(12)(13) and remodeling (14)(15)(16), protein sorting (17)(18)(19)(20), and vesicle traffic (21,22).…”

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confidence: 99%

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Dyggve–Melchior–Clausen syndrome: Chondrodysplasia resulting from defects in intracellular vesicle traffic

Osipovich

Jennings

Lin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia are recessive spondyloepimetaphyseal dysplasias caused by lossof-function mutations in dymeclin (Dym), a gene with previously unknown function. Here we report that Dym-deficient mice display defects in endochondral bone formation similar to that of DyggveMelchior-Clausen syndrome and Smith-McCort dysplasia, demonstrating functional conservation between the two species. Dymmutant cells display multiple defects in vesicle traffic, as evidenced by enhanced dispersal of Golgi markers in interphase cells, delayed Golgi reassembly after brefeldin A treatment, delayed retrograde traffic of an endoplasmic reticulum-targeted Shiga toxin B subunit, and altered furin trafficking; and the Dym protein associates with multiple cellular proteins involved in vesicular traffic. These results establish dymeclin as a novel protein involved in Golgi organization and intracellular vesicle traffic and clarify the molecular basis for chondrodysplasia in mice and men.bone formation ͉ gene trap mutation ͉ Golgi ͉ proteomics ͉ growth plate M ost mammalian growth occurs ex utero and requires extensive endochondral bone formation, a spatially organized process orchestrated by proliferating growth plate chondrocytes that subsequently differentiate and undergo apoptosis and ossification (1, 2). Inherited defects in bone formation, or osteochondrodysplasias, are responsible for more than 200 clinically distinct diseases that occur with a cumulative incidence exceeding 1 in 10,000 live births (3, 4) caused by mutations in processes critical for osseous bone formation and maintenance. These include growth factor signaling (5), extracellular matrix synthesis (6-13) and remodeling (14-16), protein sorting (17)(18)(19)(20), and vesicle traffic (21,22).Dyggve-Melchior-Clausen syndrome (DMC) and SmithMcCort dysplasia (SMC) are recessive spondyloepimetaphyseal dysplasias caused by loss-of-function mutations in dymeclin (Dym) (23-25). However, the functions of the DYM gene and the molecular mechanisms responsible for DMC and SMC have not been determined. Aside from potential membrane-spanning sequences, N-myristoylation, and protein trafficking (dileucine) motifs (26), the 74-kDa DYM protein lacks features that would guide predictions as to its functions (23,25). In addition to being structurally unique, DYM protein sequences are shared only by interspecies orthologues, and no related sequences are present in the Saccharomyces cerevisiae genome.The present study used genetic and proteomic strategies developed to analyze genes, like Dym, that have been identified by genome sequencing and whose functions are unknown (27)(28)(29). In the present study, dymeclin functions were analyzed starting with a mutation induced by gene trapping in murine ES cells (30) and subsequently introduced into the mouse germline. Dym-deficient mice developed chondrodysplasia similar to that of DMC and SMC, providing a murine model of the human diseases and demonstrating functional conservation between the mouse and ...

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Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 99%

Dyggve–Melchior–Clausen syndrome: Chondrodysplasia resulting from defects in intracellular vesicle traffic

Osipovich

Jennings

Lin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The major CNBr-peptides from the patient's type II collagen also ran more slowly than their counterparts from control cartilage (Fig. 5 b), which suggests from past experience a degree ofposttranslational overmodification (18). Peptides CB1O and CB 1 1, which lie respectively COOH-terminal and NH2-terminal to the peptide a 1(II)CB8 containing the mutation (19), were both affected.…”

Section: Resultsmentioning

confidence: 94%

Cartilage expression of a type II collagen mutation in an inherited form of osteoarthritis associated with a mild chondrodysplasia.

1991

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In a family who expressed severe dominantly inherited osteoarthritis, the underlying mutation was traced by genomic sequencing to a single base change which predicts an amino acid substitution of cysteine for arginine at residue 519 of the triple-helical domain of the type II collagen molecule (AlaKokko, L., C. T. Baldwin, R. W. Moskowitz, and D. J. . Proc. NatL Acad. Sci. USA. 87:6565-6568). In the present study we examined whether this predicted protein phenotype was evident in articular cartilage obtained from an affected family member who underwent hip surgery. The cartilage collagen was solubilized by CNBr digestion. Cysteine residues were labeled by reduction and alkylation with 14C-iodoacetate. Collagen CNBr-peptides were fractionated by ion exchange and reverse phase column chromatography. One peptide from the al(II) chain, al(II) CB8, was found to be radiolabeled. Tryptic peptides were prepared from it and identified by microsequence analysis. The results show that approximately one-quarter of the al(II) chains present in the polymeric extracellular collagen of the patient's cartilage contained the Ar&g19-to-Cys substitution. The protein exhibited other abnormal properties including disulfide-bonded al(II)-dimers and signs of posttranslational overmodification. The premature cartilage failure and osteoarthritis are presumably a result of the abnormal type II collagen being expressed in the cartilage matrix. (J. Clin. Invest. 1991. 87:357-361.)

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“…Since type II collagen is found in a restricted set of tissues that includes articular cartilage, the nucleus pulposus of the spine, and the vitreous of the eye (2), the concordance between the clinical findings and the distribution of the protein suggests that a primary defect of type II collagen may be responsible for some of these disorders. Structurally abnormal type II collagen has been isolated from cartilage ofindividuals with SED (3, 4), spondyloepimetaphyseal dysplasia (3,4), and achondrogenesishypochondrogenesis (5). Combined with the demonstration of linkage of markers in the COL2AJ gene with a form of familial osteoarthritis (6) and with Stickler syndrome (7,8), these studies have suggested that mutations in the type II collagen gene may underlie a spectrum of disorders that span a broad range of clinical severity.…”

mentioning

confidence: 99%

“…Biochemical studies have shown that cartilage from individuals with either SED (3,4) or achondrogenesis-hypochondrogenesis (5) contains type II collagen with both slowly migrating and normally migrating al(II) chains. Amino acid analyses of the abnormal type II collagen from the affected individuals have shown that there is increased lysyl hydroxylation (3)(4)(5), suggesting that the more slowly migrating population is derived from molecules containing a chain with a defect that affects triple-helix structure and/or assembly. These results are conceptually homologous to the consequences of defects in type I collagen that produce osteogenesis imperfecta, in which mutations that alter triple-helix structure result in excessive posttranslational modification of all chains in molecules that incorporate at least one abnormal chain (10,11).…”

mentioning

confidence: 99%

Tandem duplication within a type II collagen gene (COL2A1) exon in an individual with spondyloepiphyseal dysplasia.

Tiller

Rimoin

Murray

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

116

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We have characterized a mutation in the type II collagen gene (COL2AJ) that produces a form of spondyloepiphyseal dysplasia. The mutation is an internal tandem duplication of 45 base pairs within exon 48 and results in the addition of 15 amino acids to the triple-helical domain of the al chains of type II collagen derived from the abnormal allele.Although the repeating (Gly-Xaa-Yaa)1. motif that characterizes the triple-helical domain is preserved, type H collagen derived from cartilage of the affected individual contains a population with excessive posttranslational modification, consistent with a disruption in triple-helix structure. The mutation is not carried by either parent, indicating that the phenotype in the affected individual is due to a new dominant mutation. DNA sequence homology in the area of the duplication suggests that the mutation may have arisen by unequal crossover between related sequences, a proposed mechanism in the evolution and diversification of the collagen gene family.The spondyloepiphyseal dysplasias (SEDs) are a heterogeneous subgroup of the skeletal dysplasias whose cardinal features include abnormal epiphyses, flattened vertebral bodies, and ocular involvement that ranges from myopia to vitreo-retinal degeneration (1). Since type II collagen is found in a restricted set of tissues that includes articular cartilage, the nucleus pulposus of the spine, and the vitreous of the eye (2), the concordance between the clinical findings and the distribution of the protein suggests that a primary defect of type II collagen may be responsible for some of these disorders. Structurally abnormal type II collagen has been isolated from cartilage ofindividuals with SED (3, 4), spondyloepimetaphyseal dysplasia (3,4), and achondrogenesishypochondrogenesis (5). Combined with the demonstration of linkage of markers in the COL2AJ gene with a form of familial osteoarthritis (6) and with Stickler syndrome (7,8), these studies have suggested that mutations in the type II collagen gene may underlie a spectrum of disorders that span a broad range of clinical severity.Type II collagen is a fibrillar collagen that in its mature form is a homotrimer ofal(II) chains (9). Biochemical studies have shown that cartilage from individuals with either SED (3, 4) or achondrogenesis-hypochondrogenesis (5) contains type II collagen with both slowly migrating and normally migrating al(II) chains. Amino acid analyses of the abnormal type II collagen from the affected individuals have shown that there is increased lysyl hydroxylation (3-5), suggesting that the more slowly migrating population is derived from molecules containing a chain with a defect that affects triple-helix structure and/or assembly. These results are conceptually homologous to the consequences of defects in type I collagen that produce osteogenesis imperfecta, in which mutations that alter triple-helix structure result in excessive posttranslational modification of all chains in molecules that incorporate at least one abnormal chain (10, 11). Th...

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Abnormal Type II Collagen in the Spondyloepiphyseal Dysplasias

Cited by 52 publications

References 12 publications

Dyggve–Melchior–Clausen syndrome: Chondrodysplasia resulting from defects in intracellular vesicle traffic

Dyggve–Melchior–Clausen syndrome: Chondrodysplasia resulting from defects in intracellular vesicle traffic

Cartilage expression of a type II collagen mutation in an inherited form of osteoarthritis associated with a mild chondrodysplasia.

Tandem duplication within a type II collagen gene (COL2A1) exon in an individual with spondyloepiphyseal dysplasia.

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