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PubMed1994

Membrane association and oligomeric organization of the alpha and beta subunits of mouse meprin A.

Meprins are oligomeric cell surface metalloproteinases of the "astacin family." They consist of two types of subunits (alpha and beta), which are evolutionarily related and whose cDNA sequences predict a similar domain structure. The present work shows that reducing agents solubilized meprin alpha subunits (approximately 90%), but not beta subunits, from mouse kidney brush border membranes. In addition, immunoblotting of membranes or purified meprins with an antibody raised to the alpha subunit epidermal growth factor-like domain, predicted to be near the COOH terminus from the cDNA-deduced amino acid sequence, indicated that this domain is not present in the mature alpha subunit. By contrast, an epitope predicted to be near the COOH terminus of the beta subunit was present in the mature form of beta. When meprins were solubilized from brush border membranes by papain, the size of the alpha subunit (approximately 90 kDa) did not change, while the beta subunit decreased from 110 to 90 kDa with concomitant loss of the COOH-terminal epitope. These data indicate that beta is a type I transmembrane protein, while alpha does not transverse the membrane and its association is dependent on disulfide bonds. The oligomeric organization of purified meprin A (EC 3.4.24.18), examined by sedimentation equilibrium analysis and native gradient gel electrophoresis, is that of disulfide-bridged dimers which aggregate noncovalently to form higher molecular weight complexes, predominantly tetramers. Western blotting of ICR kidney brush border membrane proteins identified alpha 2 homodimers and alpha beta heterodimers. Treatment of mouse or rat kidney brush border membranes with 7 M urea solubilized alpha 2, but not alpha beta dimers. Thus, the mature alpha subunit exists in alpha 2 and alpha beta disulfide-linked dimers which form tetramers, and the alpha 2 homodimers associate with the membrane through noncovalent interactions with alpha beta.

Amino Acid Sequence↗
PubMed1994

Identification of discrete structural domains in the retinoblastoma protein. Amino-terminal domain is required for its oligomerization.

To characterize the protein product of the retinoblastoma tumor suppressor gene biochemically, a recombinant human protein was produced in an Escherichia coli expression system. The full-length protein, p110RB, and an amino-terminal truncated form, p56RB, were expressed and purified to near homogeneity by conventional chromatographic procedures. To probe the structural organization of the retinoblastoma protein the purified proteins were subjected to partial proteolysis by trypsin, chymotrypsin, and subtilisin. Four discrete structural domains were revealed in p110RB by this method. Two of these structural domains, found in both p56RB and p110RB, were mapped to the carboxyl-terminal half of the protein and corresponded to the SV40 large T binding domains defined previously by genetic methods. In addition two distinct domains in the amino-terminal half of the protein were also defined. A potential role for these newly defined amino-terminal domains was uncovered upon analysis of the purified proteins by nondenaturing polyacrylamide gel electrophoresis. p110RB revealed multiple bands by this method, suggesting the formation of oligomeric structures by the protein, while this property was not observed for p56RB. Electron microscopy of p110RB revealed linearly extended, macromolecular structures, further supporting the formation of homologous higher order structures by the full-length retinoblastoma protein. Analysis of the interactions between retinoblastoma protein molecules using the yeast two-hybrid system confirmed that the retinoblastoma protein could self-associate and that this association was mediated by interactions between the amino- and carboxyl-terminal ends of the protein. These observations suggest that the retinoblastoma protein contains multiple structural domains with the amino-terminal domains being required for oligomerization of the full-length protein.

Amino Acid Sequence↗
PubMed1993

Oligomeric structure of bacteriophage T7 DNA primase/helicase proteins.

The oligomeric structure of bacteriophage T7 gene 4 helicase/primase proteins was investigated using protein cross-linking and high pressure gel-filtration chromatography. Studies were carried out with both 4A' and 4B proteins. 4A' is a M64L mutant of 4A which has similar helicase and primase activities as the wild-type mixture of 4A and 4B proteins (Patel, S. S., Rosenberg, A. H., Studier, F. W., and Johnson, K. A. (1992) J. Biol. Chem. 267, 15013-15021), and 4B is the smaller protein which has only helicase activity. Chemical cross-linking of 4A' and 4B proteins with dimethyl suberimidate resulted in cross-linked species ranging from dimers to hexamers and beyond. The cross-linking time course, however, indicated that hexamers were the predominant species to accumulate in both 4A' and 4B proteins. The effect of MgNTP and DNA binding on oligomerization of the gene 4 proteins was investigated using high pressure gel-filtration chromatography at increasing protein concentrations. In the absence of added ligands, close to 100 microM protein concentrations were required to form stable oligomers beyond dimers. However, in the presence of Mg-beta, gamma-methylene deoxythymidine triphosphate (nonhydrolyzable analog of dTTP), 4A' and 4B protein assembled into stable hexamers at protein concentrations less than 8 microM. Addition of single-stranded DNA further stabilized the hexamer structure. Therefore, in the presence of a 60-nucleotide-long single-stranded DNA, hexamers were observed at protein concentrations as low as 0.2 microM. Nuclease protection experiments indicated that the 4A' and 4B hexamers protect about 60-65 bases of single-stranded DNA.

Bacteriophage T7↗
PubMed1996

Calnexin and calreticulin promote folding, delay oligomerization and suppress degradation of influenza hemagglutinin in microsomes.

Calnexin (CNX) and calreticulin (CRT) are molecular chaperones that bind preferentially to monoglucosylated trimming intermediates of glycoproteins in the endoplasmic reticulum. To determine their role in the maturation of newly synthesized glycoproteins, we analyzed the folding and trimerization of in vitro translated influenza hemagglutinin (HA) in canine pancreas microsomes under conditions in which HA's interactions with CNX and CRT could be manipulated. While CNX bound to all folding intermediates (IT1, IT2 and NT), CRT was found to associate preferentially with the earliest oxidative form (IT1). If HA's binding to CNX and CRT was inhibited using a glucosidase inhibitor, castanospermine (CST), the rate of disulfide formation and oligomerization was doubled but the overall efficiency of maturation of HA decreased due to aggregation and degradation. If, on the other hand, HA was arrested in CNX-CRT complexes, folding and trimerization were inhibited. This suggested that the action of CNX and CRT, like that of other chaperones, depended on an 'on-and-off' cycle. Taken together, these results indicated that CNX and CRT promote correct folding by inhibiting aggregation, preventing premature oxidation and oligomerization, and by suppressing degradation of incompletely folded glycopolypeptides.

Animals↗
PubMed1996

Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.

The transmembrane kinase Ire1p is required for activation of the unfolded protein response (UPR), the increase in transcription of genes encoding endoplasmic reticulum (ER) resident proteins that occurs in response to the accumulation of unfolded proteins in the ER. Ire1p spans the ER membrane (or the nuclear membrane with which the ER is continuous), with its kinase domain localized in the cytoplasm or in the nucleus. Consistent with this arrangement, it has been proposed that Ire1p senses the accumulation of unfolded proteins in the ER and transmits the signal across the membrane toward the transcription machinery, possibly by phosphorylating downstream components of the UPR pathway. Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by other Ire1p molecules as a result of oligomerization. In addition to its kinase domain, a C-terminal tail domain of Ire1p is required for induction of the UPR. The role of the tail is probably to bind other proteins that transmit the unfolded protein signal to the nucleus.

Alleles↗
PubMed1996

HPV-18 E6 inhibits p53 DNA binding activity regardless of the oligomeric state of p53 or the exact p53 recognition sequence.

The E6 proteins of the oncogenic-associated human papillomavirus types 16 (HPV-16) and 18 (HPV-18) function by interfering with the normal cell cycle control mechanisms, particularly those controlled by p53. HPV E6 is able to interfere with p53 function by preventing its binding to DNA target sequences and also by labelling p53 for ubiquitin-mediated degradation. We have previously reported that certain p53 mutants, defective in oligomerisation, vary in their susceptibility to E6-directed labelling for ubiquitin-mediated degradation. In this paper we report that the strength of p53's binding to DNA is dependent upon the precise target sequence, but that E6 is able to disrupt each complex. We also report the binding of different oligomeric forms of p53 to different DNA sequences and correlate this with in vivo transcriptional activity and demonstrate the susceptibility of that DNA binding to disruption by E6. Finally we show that the ability of p53 to bind to TBP is a function of its oligomeric state and correlates in part with its ability to transrepress but not with its ability to transactivate.

Animals↗
PubMed1996

Oligomeric assembly of thrombospondin in the endoplasmic reticulum of thyroid epithelial cells.

The thyroid endoplasmic reticulum (ER) provides an environment in which conformational maturation of thyroglobulin monomers occurs with progressive dissociation from BiP (a molecular chaperone), prior to thyroglobulin dimerization. This pattern of folding is thought to represent a pathway common to many exportable polypeptides. Thyrocytes also synthesize and secrete thrombospondin, an extracellular matrix glycoprotein that forms disulfide-linked trimers. Using a monoclonal antibody recognizing the N-terminal heparin-binding domain of thrombospondin, pulse-chase/immunoprecipitation experiments indicate that this epitope forms essentially cotranslationally. Dependent upon structural information contained within the N-terminal region, thrombospondin trimers also form and are rapidly stabilized by interchain disulfide bonds in the peritranslational period. Within 30 to 60 sec, a new epitope in the mid-molecule is detected. Additional approaches (including thrombospondin dissociation from BiP-an indirect measure of conformational maturation; t1/2 approximately 20 min) independently suggest that significant folding of monomers occurs within the trimer, i.e., well after oligomerization. These later events appear rate limiting for thrombospondin export from the ER (t1/2 approximately 30 min). The results highlight plasticity in the relationship between oligomerization and specific folding events for different proteins exported from the thyroid ER.

Animals↗
PubMedDate not supplied

Pancreatic procarboxypeptidases: oligomeric structures and activation processes revisited.

The activation peptides of procarboxypeptidases of the A1 type act in a post-activation mechanism of control, limiting the expression of activity immediately after the limited proteolysis has occurred. This effect is due to structural complementarity between the enzymatic moiety and the released fragments, and is further enhanced by the occurrence of procarboxypeptidase A1 in oligomeric complexes of different type depending on the species studied. In those complexes, the activation segment has an important role in the stabilisation of the quaternary structure. The relationship between oligomeric structure and activation is reviewed here for two of the most extensively studied systems.

Animals↗
PubMed1997

[In vitro and in vivo studies on the cardioprotective action of oligomeric procyanidins in a Crataegus extract of leaves and blooms].

Cardioprotective effects of a standardized extract from leaves with flowers of Crataegus (WS-1442; content of oligomeric procyandins [OPC]: 18.75%) have recently been demonstrated in an ischemia-reperfusion model in rats. Further studies were now conducted to clarify the mechanism of action and to identify active constituents involved in these effects of WS-1442. Exhausting partitioning between ethyl acetate/water and successive ultrafiltration of the aqueous layer led to the quantitative recovery of three fractions, which were tested for their in vitro radical scavenging (RS) and human neutrophil elastase (HNE) inhibitory activity. The lipophilic ethylacetate-soluble fraction A, enriched in flavone derivatives and constituting 14.9% of WS-1442, was as active as WS-1442 in inhibiting HNE. However, its RS activity was only about half that of the primary extract. Although 67.9% of WS-1442 was recovered in a water-soluble low molecular weight fraction B, this fraction displayed only weak RS and HNE inhibiting activity. In contrast, the RS and HNE inhibiting potencies of an essentially flavone-free and OPC-rich fraction C (21.3% of WS-1442) were significantly higher (inhibition of lipid peroxidation: IC50 0.3 microgram/ml; inhibition of HNE: IC50 0.84 microgram/ml) as those of WS-1442. The RS and HNE inhibitory activities of the extract and those of its fractions correlated well with their OPC-content but not with their concentration of flavonols. These results demonstrate that OPCs of Crataegus extracts possess stronger radical scavenging activities than flavone derivatives or other constituents. In addition, the oligomeric components are potent inhibitors of HNE. Oral administration of 20 mg/kg/d of the OPC-rich fraction C to rats afforded similar protection against ischemia-reperfusion induced pathologies as treatment with WS-1442 at a dose of 100 mg/kg/d. These observations indicate that radical scavenging and elastase inhibitory activities could indeed be involved in the observed cardioprotective effects of WS-1442, and demonstrate that OPCs are major orally active constituents of WS-1442. Thus, Crataegus extracts used therapeutically for cardiovascular diseases should be analyzed and standardized for their OPC-content.

Animals↗
PubMed1998

HIV-1 neutralizing antibodies in the genital and respiratory tracts of mice intranasally immunized with oligomeric gp160.

Because mucosal surfaces are a primary route of HIV-1 infection, we evaluated the mucosal immunogenicity of a candidate HIV-1 vaccine, oligomeric gp160 (o-gp160). In prior studies, parenteral immunization of rabbits with o-gp160 elicited broad neutralizing serum Ab responses against both T cell line-adapted HIV-1 and some primary HIV-1 isolates. In this study, nasal immunization of mice with o-gp160, formulated with liposomes containing monophosphoryl lipid A (MPL), MPL-AF, proteosomes, emulsomes, or proteosomes with emulsomes elicited strong gp160-specific IgG and IgA responses in serum as well as vaginal, lung, and intestinal washes and fecal pellets. The genital, respiratory, and intestinal Abs were determined to be locally produced. No mucosal immune responses were measurable when the immunogen was given s.c. Abs from sera and from vaginal and lung washes preferentially recognized native forms of monomeric gp120, suggesting no substantial loss in protein tertiary conformation after vaccine formulation and mucosal administration. Inhibition of HIV-1MN infection of H9 cells was found in sera from mice immunized intranasally with o-gp160 formulated with liposomes plus MPL, proteosomes, and proteosomes plus emulsomes. Formulations of o-gp160 with MPL-AF, proteosomes, emulsomes, or proteosomes plus emulsomes elicited HIV-1MN-neutralizing Ab in lung wash, and formulations with proteosomes, emulsomes, or proteosomes plus emulsomes elicited HIV-1MN-neutralizing Ab in vaginal wash. These data demonstrate the feasibility of inducing both systemic and mucosal HIV-1-neutralizing Ab by intranasal immunization with an oligomeric gp160 protein.

Administration, Intranasal↗
PubMed1998

Dissociative thermal inactivation, stability, and activity of oligomeric enzymes.

Results of kinetic studies on dissociative thermal inactivation of oligomeric enzymes are discussed. Dissociative thermal inactivation is the process in which the kinetically irreversible protein change is preceded by a reversible stage of oligomer dissociation. In experiments, this is demonstrated by the dependence of inactivation rate on total protein concentration. This paper gives the relations which allow the calculation from experimental data the following physicochemical constants which characterize the stability of oligomeric enzymes: the constant for the rate of irreversible change of monomeric protein, the equilibrium constant for dimer dissociation, and the rate constant for dimer dissociation. The problem of a "conformational lock", the contact between protein globules that admits a multistep destruction of active oligomer and explains the induction period occurring in kinetic thermal inactivation curves, is discussed. The X-ray structural analyses for several dimeric enzymes, i.e., alkaline phosphatase (EC 3.1.3.1) from E. coli, alcohol dehydrogenase (EC 1.1.1.1) from horse liver, and baker's yeast enolase (EC 4.2.1.11), explain why they lose catalytic activity during the dissociation of the protein into monomers and also provide a physically reasonable picture of the structure of their conformational lock. Also, these data support the kinetic scheme used to describe the dissociative inactivation of dimeric enzymes.

Alcohol Dehydrogenase↗
PubMed1998

Structural properties of staphylococcal nuclease in oligomeric A-forms.

Association affects the structural properties of different partially folded conformations of staphylococcal nuclease induced by anions of different nature. It is shown that oligomerization induces new structural levels in non-native A-forms. A close structural similarity between the monomeric A2 and the dimeric (A1)2 forms as well as between the monomeric A3 and oligomeric [(A1)2]M and [A2]M forms is established. This suggests that association of a protein molecule in partially folded conformations can be an additional structure forming factor.

Anions↗
PubMed1998

Identification of twelve mutations in cartilage oligomeric matrix protein (COMP) in patients with pseudoachondroplasia.

Pseudoachondroplasia (PSACH) is an autosomal dominant dwarfing condition characterized by disproportionate short stature, joint laxity, and early-onset osteoarthrosis. PSACH is caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). We are reporting on mutations in COMP in 12 patients with PSACH, including ten novel mutations. Eleven of the mutations are in exons 17A, 17B, and 18A, which encode the calcium-binding domains, and one mutation is in exon 19, which encodes part of the carboxy-terminal globular domain. Two of the mutations identified are the common delGAC(1430-1444) in exon 17B, which accounts for 36% of identified PSACH mutations. This report increases the range of mutations in COMP that cause PSACH and provides additional evidence for the importance of the calcium-binding domains and the globular domain to the function of COMP.

Achondroplasia↗
PubMed1999

Identification of nine novel mutations in cartilage oligomeric matrix protein in patients with pseudoachondroplasia and multiple epiphyseal dysplasia.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1) are allelic disorders caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). PSACH is a dominant condition characterized by disproportionate short stature, joint laxity, and early-onset osteoarthritis. EDM1 is a less severe skeletal dysplasia associated with average to mild short stature, joint pain, and early-onset osteoarthritis. COMP is an extracellular matrix protein present in cartilage, ligament, and tendon tissues. Here, we report on nine novel mutations in COMP causing PSACH and EDM1. Four of these mutations are in exons 13C and 14 where no previous mutations had been reported. One of those mutations was identified in two separate EDM1 families. In addition, we have identified the first case of PSACH resulting from an expansion of the five aspartates in exon 17B. We are also reporting a mutation in a third PSACH family with somatic/germline mosaicism. Therefore, this report increases the range of mutations that cause PSACH and EDM1 and provides additional regions to target for mutational analysis.

Achondroplasia↗
PubMed1998

Increased serum levels of cartilage oligomeric matrix protein in chronic erosive arthritis in rats.

OBJECTIVE: To investigate the utility of serum cartilage oligomeric matrix protein (COMP) for disease monitoring in rats with chronic pristane-induced arthritis, and to examine the influence of age, sex, and genes on COMP concentrations in rat serum. METHODS: Serum COMP levels were quantified by immunoassay. Sera were obtained from DA, E3, and (E3 x DA)F1 rats each week between the ages of 4 and 30 weeks. The (E3 x DA)F2 (second generation after intercrossing) rats were injected intradermally with the synthetic oil pristane. Arthritis was monitored by a macroscopic scoring system, and serum levels of COMP were measured on days 6, 35, and 49 after immunization. RESULTS: Serum levels of COMP decreased during growth, and reached a plateau after the age of 12 weeks. The DA rats had higher COMP levels than the E3 rats, and the (E3 x DA)F1 rats had intermediate levels. No differences were observed in these levels when the rats were grouped by sex. Arthritic (E3 x DA)F2 rats had increased serum concentrations of COMP on days 35 and 49 after pristane injection (P < 0.0001 versus the nonarthritic animals). COMP levels correlated with the severity of macroscopically detectable arthritis at both time points (r > 0.9). Rats with a chronic disease course were distinguished by higher serum concentrations of COMP during the acute stage than animals with similar clinical scores but with resolving arthritis (P < 0.01). CONCLUSION: Serum analyses of COMP offer promise for monitoring tissue involvement in experimental arthritis. Such analyses should be useful for monitoring therapeutic interventions aimed at retarding tissue destruction as well as for studies of the genetically determined regulation of COMP turnover and susceptibility to arthritis. The application of molecular marker measurements to experimental arthritis offers a new possibility for verifying the utility of such measurements in human arthritis.

Animals↗
PubMed1998

Regulation of cartilage oligomeric matrix protein synthesis in human synovial cells and articular chondrocytes.

OBJECTIVE: Cartilage oligomeric matrix protein (COMP) is a component of the extracellular matrix of articular cartilage. Its increased presence in synovial fluid and serum has been associated with accelerated joint damage in patients with rheumatoid arthritis (RA) and osteoarthritis. To fully understand the reasons for fluctuations of COMP levels, we studied the biosynthesis of this molecule in cells derived from joint tissues. METHODS: Synovial cells were derived from synovial tissues of patients with RA, and human articular chondrocytes were prepared from normal articular cartilage. Analysis by Northern blotting was used to evaluate steady-state levels of COMP messenger RNA (mRNA), while secretion of the protein into culture media was analyzed by Western blotting. Expression of COMP in synovial tissues was studied by reverse transcriptase-polymerase chain reaction analysis and by in situ hybridization. RESULTS: COMP was synthesized and secreted by synovial cells as well as by articular chondrocytes in culture. The basal rate of synthesis was very low; however, COMP biosynthesis in both cell populations was induced very strongly by transforming growth factor beta1 (TGFbeta1). Interleukin-1beta counteracted COMP induction by TGF-beta1. COMP was not detected in culture media of skin or fetal lung fibroblasts, either in the absence or the presence of TGFbeta1. COMP mRNA was also present in fresh synovial tissue specimens obtained from patients with RA. CONCLUSION: COMP is synthesized and secreted not only by articular chondrocytes, but also by synovial fibroblasts. The demonstration of COMP expression in surgical specimens of synovial tissues suggests that the inflamed synovium may provide an additional source for the elevated levels of COMP observed in arthritis. Thus, increased COMP levels in body fluids may be indicative of active synovitis as well as of accelerated joint erosion.

Cartilage Oligomeric Matrix Protein↗
PubMed1999

Serum cartilage oligomeric matrix protein reflects osteoarthritis presence and severity: the Johnston County Osteoarthritis Project.

OBJECTIVE: To characterize serum cartilage oligomeric matrix protein (COMP) levels by age and gender for a radiographically defined population free of hip and knee osteoarthritis (OA), and to examine the potential utility of COMP as a diagnostic biomarker for knee OA. METHODS: Serum samples and knee and hip radiographs were obtained at a baseline evaluation as part of the Johnston County Osteoarthritis Project, a population-based study of OA in rural North Carolina. A total of 291 Caucasian participants were randomly selected for COMP analysis, 143 patients with radiographic knee OA (Kellgren/Lawrence [K/L] grade > or = 2) and 148 controls with neither hip nor knee OA (K/L grade 0), evenly distributed by age and gender. COMP was quantified by competitive enzyme-linked immunosorbent assay with monoclonal antibody 17-C10. The natural log-transformed COMP data were analyzed using general linear models. RESULTS: Serum COMP levels were significantly elevated (P = 0.0001) in the age > or = 65 group (mean +/- SD 1,302.1 +/- 496.7 ng/ml) versus the age 45-54 and age 55-64 groups (1,058.1 +/- 432.4 and 1,038.6 +/- 313.3, respectively). Serum COMP levels of the OA group were significantly higher than those of the control group (1,208.57 +/- 487.47 ng/ml versus 1,061.83 +/- 370.58 ng/ml; P = 0.0093). Serum COMP levels also increased significantly with knee OA K/L grade (P = 0.0047), knee OA laterality (P = 0.0043), and number of knee and hip joints involved (P = 0.0001). There was no significant difference in serum COMP levels by gender or obesity. CONCLUSION: We demonstrate that in a population-based sample, serum COMP levels can distinguish an OA-affected subgroup from an unaffected subgroup and can reflect disease severity and multiple joint involvement in OA.

Aged↗
PubMed2001

Novel mutation in exon 18 of the cartilage oligomeric matrix protein gene causes a severe pseudoachondroplasia.

Pseudoachondroplasia (PSACH) is a common skeletal dysplasia characterized by disproportionate short stature, early-onset osteoarthrosis, and dysplasia of the spine, epiphysis, and metaphysis. Multiple epiphyseal dysplasia (MED) is a similar but less severe disorder characterized by dysplasia of the epiphysis. Both disorders are caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. COMP mutations cluster in a region of the gene that encodes calmodulin-like repeats (CLRs) and correlate closely with disease severity. Typically, mutations in exon 13 that composes the seventh CLR produce severe PSACH phenotypes, whereas mutations found elsewhere in the gene produce mild PSACH or MED phenotypes. We have identified a PSACH patient carrying a novel mutation in exon 18 of COMP that composes the C-terminal globular domain. This mutation produced a severe PSACH phenotype with marked short stature and deformities of the spine and extremities. Our results extend the range of disease-causing mutations within the COMP gene and demonstrate the importance of the additional domain of COMP protein in its in vivo function.

Achondroplasia↗