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Biomedical subjects

V H Rao

Publications and source records attributed to V H Rao.

At least 19 recordsLinked to original sources
PubMed2005

Conventional slow freezing, vitrification and open pulled straw (OPS) vitrification of rabbit embryos.

Three different methods of cryopreservation viz., conventional slow freezing, vitrification and open pulled straw vitrification were compared for their ability to support post thaw in vitro and in vivo development of rabbit embryos. Morula stage rabbit embryos were collected from super-ovulated donor does. They were randomly allocated to different freezing methods and stored up to 3 months in liquid nitrogen. After thawing and removal of cryoprotectants, embryos exhibiting intact zona pellucida and uniform blastomeres were considered suitable for in vitro culture and/or transfer. Three to five cryopreserved embryos placed in approximately 1 ml of culture medium (TCM 199 supplemented with foetal calf serum and antibiotics) were incubated for up to 72 h under humidified atmosphere of 5% CO2 in air at 39 degrees C. Development to hatched blastocyst stage was considered the initial indicator of success of cryopreservation of embryos. Of the embryos cryopreserved by programmed freezing, open pulled straw vitrification, vitrification-55 h pc and vitrification-72 h pc 55, 71, 17 and 48%, respectively, developed into hatched blastocysts. Similarly 19, 29, and 4% of embryos cryopreserved by programmed freezing, open pulled straw vitrification and vitrification -72 h pc developed into live offspring on transfer to recipient does. This is the first report on open pulled straw vitrification of rabbit embryos. Present results, suggest that (a) open pulled straw vitrification supports better in vitro survival of frozen thawed rabbit morulae; (b) both programmed freezing and OPS are similar but superior to vitirification in supporting in vivo survival of frozen thawed rabbit embryos.

Animals↗
PubMed1999

Interleukin-1beta upregulates MMP-9 expression in stromal cells of human giant cell tumor of bone.

Giant cell tumor (GCT) of bone is a progressive, potentially malignant process that destroys skeletal tissue. It consists of multinucleated giant cells, which are hypothesized to be derived from a monocyte/macrophage lineage and mononuclear stromal cells, and the precise relationship of these cells is not fully understood. Recently, we demonstrated that the production of matrix metalloproteinase-9 (MMP-9) in GCT stromal cells is regulated by certain factor(s) secreted by the multinucleated giant cells. In the present study, we evaluated for the presence of interleukin-1beta (IL-1beta) and attempted to establish its possible role for the induction of MMP-9 in GCT stromal cells. Using enzyme-linked immunosorbent assay (ELISA), we have demonstrated that the primary GCT cultures secrete both IL-1beta and MMP-9. The addition of monoclonal antibody (mAb) against IL-1beta partially abrogated, but did not abolish, MMP-9 expression. Our results on gelatin zymography, reverse transcriptase-polymerase chain reaction (RT-PCR), and immunofluorescence showed that GCT stromal cells did not express MMP-9, although treatment with IL-1beta induced MMP-9 expression in a dose-dependent manner, and the secretion peaked 24 h after stimulation and then plateaued. Studies with cycloheximide, a protein synthesis inhibitor, demonstrated that de novo protein synthesis is required for IL-1beta induced MMP-9 expression. Moreover, nuclear run-on analysis has revealed that IL-1beta significantly increased MMP-9 gene transcription in GCT stromal cells. The data suggest that IL-1beta secreted by the multinucleated giant cells in GCT may be one of the factors responsible for the induction of MMP-9 at the transcriptional level in GCT stromal cells in vivo. We conclude that GCT has a self-stimulatory system for the production of MMP-9, and the ability of stromal cells to produce MMP-9 with appropriate stimuli, such as IL-1beta, and possibly in concert with other cytokines may contribute to the aggressive and potentially malignant behavior of GCT.

Enzyme-Linked Immunosorbent Assay↗
PubMed1999

Transcriptional regulation of MMP-9 expression in stromal cells of human giant cell tumor of bone by tumor necrosis factor-alpha.

We determined whether certain factor(s) secreted by multinucleated giant cells, which is of monocyte/macrophage lineage in giant cell tumor of bone (GCT), regulate the induction of matrix metalloproteinase (MMP)-9 expression in mononucleated stromal cells. Our data derived using enzyme linked immunosorbant assays (ELISAs) suggest that the GCT cells in primary culture produce both MMP-9 and tumor necrosis factor-alpha (TNF-alpha). Further, the MMP-9 expression in GCT primary cultures was partially abrogated by neutralizing antibody to TNF-alpha, suggesting that TNF-alpha secretion by the multinucleated giant cells may be one of the factors responsible for the production of MMP-9 by the stromal cells in vivo. In order to confirm this we examined the role of TNF-alpha on the induction of MMP-9 expression in bone GCT stromal cells. These cells express MMP-2, but not MMP-9. However, treatment of these cells with TNF-alpha induced the expression of MMP-9 in a concentration-dependent manner. Kinetic experiments revealed that the secretion of MMP-9 peaked 12 h post TNF-alpha stimulation. Immunofluorescence studies confirmed the expression of MMP-9 after stimulation of GCT stromal cells with TNF-alpha. Further, TNF-alpha-induced MMP-9 expression was completely blocked with neutralizing antibody to TNF-alpha, thereby demonstrating the specificity. In addition, the induction of MMP-9 expression by TNF-alpha was completely abrogated in the presence of cycloheximide, a protein synthesis inhibitor, suggesting that de novo protein synthesis may be required. Nuclear run-on analysis demonstrated that treatment of GCT stromal cells significantly enhanced the MMP-9 gene transcription. Together, our data suggest that TNF-alpha secreted by the multinucleated giant cells up-regulates MMP-9 expression in GCT stromal cells by the induction of certain transcription factors, which in turn enhanced the rate of transcription of MMP-9 gene. These studies also suggest the existence of an essential cell-cell interaction in the regulation of MMP-9 expression in GCT.

Adult↗
PubMed1998

Accelerated linear growth and advanced bone age in Sotos syndrome is not associated with abnormalities of collagen metabolism.

OBJECTIVES: To investigate whether the advanced bone age in Sotos syndrome is associated with alterations in type I collagen metabolism in bone. DESIGN AND METHODS: The metabolism of collagen was studied by analyzing the production, gene expression and degradation of type I collagen in dermal fibroblast strains from patients with Sotos syndrome and comparing them with fibroblasts from age-matched healthy subjects. Collagen production was determined as collagenase digestible radioactivity and collagen mRNA levels were measured by RT-PCR. Collagen degradation was assessed by specific collagenase assay and gelatin zymography. To determine the structural defects in type I collagen, the newly synthesized proteins were analyzed by SDS-PAGE before and after proteolytic digestion with pepsin. RESULTS: In the present study, we have demonstrated that the collagen production, secretion and degradation in Sotos syndrome is comparable to controls. In addition, no qualitative differences in mRNA transcripts for type I collagen were detected between the control and Sotos syndrome fibroblasts. The secretion and intracellular accumulation of procollagen is also comparable to controls. The analysis of both procollagen and collagen on SDS-PAGE did not exhibit any major structural changes as compared with controls. CONCLUSIONS: Our results on several aspects of collagen metabolism have demonstrated for the first time that collagen, the most abundant of mammalian proteins and the major constituent of bone, is normal in patients with Sotos syndrome. Therefore, it appears that the advanced bone age and accelerated linear growth seen in patients with Sotos syndrome may not be attributed to inherent abnormalities of collagen metabolism. The etiology and the pathogenesis of Sotos syndrome still remains unclear.

Adolescent↗
PubMed1997

Regulation of MMP-9 (92 kDa type IV collagenase/gelatinase B) expression in stromal cells of human giant cell tumor of bone.

Matrix metalloproteinases (MMPs) play an important regulatory role in tissue morphogenesis, cell differentiation, tumor invasion and metastasis. Several authors have reported a direct correlation between the production of 72 kDa (MMP-2) and 92 kDa (MMP-9) type IV collagenases/gelatinases and the metastatic potential of cancer cells. Recently, we have identified the expression of both MMP-2 and MMP-9 in primary cultures of human giant cell tumor (GCT) of bone in vitro, and in tissue extracts in vivo. Interestingly, MMP-9 is not secreted by late-passaged GCT cells. It is possible that the production of MMP-9 is regulated by certain factor(s) secreted by the multinucleated giant cells in the primary culture. In order to test this hypothesis, the effect of primary-culture-conditioned medium on the expression of MMP-9 by late-passaged mononuclear stromal cells was examined. Adding conditioned medium from the primary GCT culture to the late-passaged stromal cells induced MMP-9, as evidenced by the presence of lytic bands at M(r) 92,000 and 72,000 on a gelatin zymogram. These enzyme activities were inhibited by EDTA, a well-known inhibitor of the MMPs. We confirmed these results by Western blotting using specific antibodies and RT-PCR for MMP-2 and MMP-9. Immunofluorescence studies with specific antibodies to MMP-9 further confirmed its expression by the passaged stromal cells cultured in the primary-culture-conditioned medium. The data indicate that MMP-2 and MMP-9 are produced by the mononuclear stromal cells when cultured in GCT primary-culture-conditioned medium. This suggests that multinucleated giant cells in primary cultures secrete a factor(s) that stimulates stromal cells to produce MMP-9, which, in turn, may contribute to the aggressive behavior of GCT.

Adolescent↗
PubMed1996

Expression and localization of 92 kDa type IV collagenase/gelatinase B (MMP-9) in human gliomas.

Matrix metalloproteinases play an important regulatory role in tissue morphogenesis, cell differentiation and motility, and tumor cell invasiveness. We have recently demonstrated elevated activity of the 92 kDa type IV collagenase (MMP-9) in human glioblastoma and in the present study examine the relative amounts of MMP-9 protein and mRNA in human gliomas and as well as the distribution of MMP-9 in human glioma tumors in vivo. Using an enzyme-linked immunosorbent assay for the quantitative determination of MMP-9 protein, we found that levels were significantly higher in malignant astrocytomas, especially in glioblastoma multiforme, than in normal brain tissues and low-grade gliomas. In addition, the amount of MMP-9 mRNA, as determined by northern blot analysis was higher in anaplastic astrocytomas and glioblastoma multiforme than in normal brain tissue and low-grade gliomas. Immunocytochemical staining for MMP-9 showed strong cytoplasmic immunoreactivity in the tumor cells and the proliferating endothelial cells of glioblastoma multiforme and anaplastic astrocytomas. The staining intensity was lowe in low-grade astrocytomas, and was undetectable or very low in normal brain astrocytes. The results indicate that expression of MMP-9 is dramatically upregulated in highly malignant gliomas and correlates with the highly malignant progression of human gliomas in vivo, and support a role for the MMP-9 in facilitating the invasiveness seen in malignant gliomas in vivo.

Amino Acid Sequence↗
PubMed1995

Expression of 72 kDa and 92 kDa type IV collagenases from human giant-cell tumor of bone.

Basement membrane forms widespread barriers to tumor invasion. It has been shown that tumor-secreted, basement membrane-degrading enzymes, namely metalloproteinases (MMPs) play an important role in tumor invasion and metastasis. In this study, we determined the enzymatic activity, content, and mRNA of both the 72 kDa (MMP-2) and 92 kDa (MMP-9) MMPs in primary cultures of human giant-cell tumor of bone (GCT) in vitro and in tissue extracts (in vivo). Gelatin zymography showed the presence of lytic bands at M(r) 121,000, 92,000, and 72,000, and these enzymatic activities were inhibited by EDTA, an inhibitor of MMPs. Western blots with antibodies specific for MMP-2 and MMP-9 confirmed the presence of MMP-2 and MMP-9 both in vitro and in vivo, but GCT cells at late passage showed only MMP-2. Northern blots using labeled cDNA probes specific for these molecules revealed the presence of 3.1 kb transcript for MMP-2 and a 2.9 kb transcript for MMP-9. Using specific antibodies to 72 kDa and 92 kDa type IV collagenases, we studied their cellular distribution by immunohistochemical means. Stronger immunoreactivity was found for 92 kDa type IV collagenase than 72 kDa type IV collagenase in the giant cells. It appears, therefore, that MMP-9 may play an important role in the malignant behavior of GCTs and suggests a potential therapeutic role for protease inhibitors in attempting to minimize the invasive behavior of GCTs.

Bone Neoplasms↗
PubMed1994

Expression and localization of urokinase-type plasminogen activator receptor in human gliomas.

Urokinase-type plasminogen activator receptors (uPARs) play an important role in tumor invasion by localizing degradative enzymes at the invasive zone. In the present study, we examined the presence and distribution of uPARs in human gliomas in vivo. The amounts of uPARs were measured by radioreceptor assays and Northern blotting and were significantly higher in anaplastic astrocytomas and glioblastomas than they were in normal brain tissues and low-grade gliomas. In situ hybridization was performed to investigate the cellular source of uPAR mRNA in various types of astrocytomas and normal brain tissues. uPAR mRNA was localized in astrocytoma cells and endothelial cells within tumor tissue, especially near sites of vascular proliferation and at the leading edges of tumors. uPAR mRNA was also expressed in tumor cells near necrotic areas. Expression was barely detectable in low-grade astrocytomas and normal brain tissues. These results suggest that expression of uPAR in the invading astrocytoma cells may play a significant role in the invasive behaviors of glioblastomas.

Base Sequence↗
PubMed1994

Expression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo.

Plasminogen activators regulate a variety of processes involved in tissue morphogenesis, as well as cell differentiation, migration, and invasion. We examined the relative amounts of mRNA and protein and localization of urokinase-type plasminogen activator (uPA) in human astrocytomas in vivo. Using fibrin zymography and densitometric quantitation, we found that uPA activity was significantly higher in malignant astrocytomas, especially in glioblastomas, than it was in normal brain tissues or low-grade gliomas. The amounts of uPA mRNA, as determined by Northern blot analysis, were higher in anaplastic astrocytomas and glioblastomas than in normal brain tissues and low-grade gliomas, consistent with the amount of uPA activity. To investigate the cellular source of uPA in various tissues, we performed immunocytochemical localization of uPA protein and in situ hybridization of uPA mRNA with astrocytomas and normal brain tissues. Immunocytochemical staining for uPA showed strong immunoreactivity in the tumor cells and vasculature of glioblastomas and anaplastic astrocytomas but undetectable or very low immunoreactivity for uPA in low-grade gliomas and normal brain tissues. uPA mRNA was located in astrocytoma and endothelial cells and was heterogeneously distributed within glioblastoma, with preferential localization near vascular proliferation and at the leading edge of the tumor. uPA expression was dramatically higher in highly malignant astrocytomas, especially glioblastomas, and was correlated with malignant progression of astrocytomas.

Astrocytoma↗
PubMed1994

Expression and cellular localization of messenger RNA for plasminogen activator inhibitor type 1 in human astrocytomas in vivo.

We investigated the expression and cellular localization of plasminogen activator inhibitor type 1 (PAI-1) in human astrocytoma in vivo. Northern blot and densitometric quantitation of PAI-1 mRNA indicated that PAI-1 transcripts were significantly higher in human malignant astrocytomas and especially in glioblastomas than in low-grade gliomas and normal brain tissues in vivo. Using in situ hybridization with paraffin-embedded surgical specimens of human gliomas and normal brain tissues, PAI-1 mRNA was abundantly expressed in glioblastomas. PAI-1 mRNA was localized mainly in tumor cells and endothelial cells. The distribution of PAI-1 mRNA expression was particularly abundant around areas of vascular proliferation and in remnant tumor cells surrounding necrotic foci. PAI-1 mRNA was also expressed in both the tumor and endothelial cells of anaplastic astrocytomas, whereas it was not expressed or only weakly expressed in low-grade astrocytomas or normal brain tissues. These results suggest that high expression of PAI-1 is associated with the malignant progression of astrocytic tumors and that excessive PAI-1 expression might be associated with intratumoral necrosis in glioblastomas.

Astrocytoma↗
PubMed1994

Sequential acquisition of transcriptional control during early embryonic development in the rabbit.

Regulation of gene expression during early embryonic development in the rabbit was investigated by quantitative assay of firefly luciferase activity obtained by microinjection of three plasmid constructs using the regulatory region of polyomavirus promoter (PrPyV) with two different enhancer sequences (wild type or mutant "embryo-responsive," ER2) coupled to this reporter gene. Following injection at the 1-cell stage maximal level of expression of these genes was reached after three cell cycles. Two important regulatory steps that progressively limited gene expression were identified: the passage through the first mitosis and the transition from maternal to zygotic control of development (MZT) described at the 8- to 16-cell stage. The completion of the first mitosis was associated with the requirement of an enhancer sequence to stimulate expression of the weak PrPyV promoter while beyond the MZT, only particular enhancer sequences, such as ER2, allowed maintainance of the expression of PrPyV promoter. In addition, comparison of expression of constructs injected in pronuclei, 2-cell embryonic nuclei, and transplanted 32-cell blastomeres revealed that the nuclear environment could be a major effector in the regulation of embryonic gene expression. A schematic view is proposed describing the sequential establishment of the regulation exerted on early embryonic gene expression in progress from the onset of the zygotic genome activity to the MZT.

Animals↗
PubMed1994

Activities, localizations, and roles of serine proteases and their inhibitors in human brain tumor progression.

The plasminogen activation system consists of plasminogen activators and their inhibitors, serine proteases, and serpins. The proteases and inhibitors regulate a variety of processes in tissue morphogenesis, differentiation, cell migration, and cancer cell invasiveness and metastasis. One of the plasminogen activators, urokinase-type plasminogen activator (uPA), binds to a specific surface and provides a localized cell surface proteolytic activity required for the destruction of extracellular matrix, which is a vital step in tumor cell invasion. The proteolytic activity of uPA is modulated by its cell surface receptor, as well as by plasminogen activator inhibitor type-1 (PAI-1) and, to a lesser degree, by other inhibitors. The role of plasminogen activators and their inhibitors in cancer invasion can be demonstrated in the development and progression of malignant brain tumors. Our findings indicate that uPA and PAI-1 expression are dramatically upregulated in malignant brain tumors in parallel with the histological progression of the tumors. The results suggest that these molecules may contribute to tumor invasion in addition to their significant role in angiogenesis. An evaluation of the plasminogen activation system could add diagnostic and prognostic significance to the evaluation of individual patients.

Brain Neoplasms↗
PubMed1993

A cysteine for glycine substitution at position 175 in an alpha 1 (I) chain of type I collagen produces a clinically heterogeneous form of osteogenesis imperfecta.

The molecular basis for Osteogenesis Imperfecta in a large kindred with a highly variable phenotype was identified by sequencing the mutant pro alpha 1 (I) protein, cDNA and genomic DNA from the proband. Fibroblasts from different affected individuals all synthesize both normal Type I procollagen molecules and abnormal Type I procollagen molecules in which one or both pro alpha 1 (I) chain(s) contain a cysteine residue within the triple helical domain. Protein studies of the proband localized the mutant cysteine residue to the alpha 1 (I) CB 8 peptide. We now report that cysteine has replaced glycine at triple helical residue 175 disrupting the invariant Gly-X-Y structural motif required for perfect triple helix formation. The consequences include post-translational overmodification, decreased thermal stability, and delayed secretion of mutant molecules. The highly variable phenotype in the present kindred cannot be explained solely on the basis of the cysteine for glycine substitution but will require further exploration.

Amino Acid Sequence↗
PubMed1993

Normal production, nature, and extent of intracellular degradation of newly synthesized collagen in fibroblasts from a patient with prolidase deficiency.

We have examined the extent of intracellular degradation of newly synthesized collagen occurring in fibroblasts from a patient with prolidase deficiency, a rare, autosomal recessively inherited disorder, in which a lack of prolidase, which normally cleaves imidodipeptides with a C-terminal Pro or Hyp residue, results in hyperimidodipeptiduria. The main clinical feature of the condition is chronic, intractable ulceration of the skin, and the suggestion has been made that it represents a specific disorder of collagen metabolism. Although most of the hydroxy-[14]proline derived from the intracellular degradation of newly synthesized collagen in prolidase-deficient fibroblasts occurred in imidodipeptides, with a similar chromatographic profile to those occurring in the patient's urine, the proportion of collagen undergoing such degradation was as in control cells. No abnormality was found in other parameters of collagen metabolism studied, and the results confirm that, although the pathogenesis of its clinical manifestations remains unclear, the disorder is one of protein degradation in general.

Carbon Radioisotopes↗
PubMed1991

Comparison of morphological and biochemical characteristics of cultured chondrocytes isolated from proliferative and hypertrophic zones of bovine growth plate cartilage.

Primary cultures of chondrocytes isolated from the proliferative and hypertrophic zones of bovine growth plate cartilage were established, and their morphological and biosynthetic characteristics were compared. High-cell-density monolayer cultures maintained a predominantly chondrocytic morphology, preserved their zone-specific collagen phenotype, and produced an abundant proteoglycan matrix. In contrast, monolayer cultures plated at low cell densities contained many cells with fibroblastic morphology and initiated the synthesis of type I collagen within 72 h following seeding. On a per cell basis, the proliferative zone chondrocytes displayed greater biosynthetic activity than chondrocytes from the hypertrophic region. Characterization of newly synthesized collagens showed that type II collagen was the major biosynthetic product of both types of cells. In contrast, type X collagen was synthesized exclusively by hypertrophic chondrocytes and represented about 20% of the total collagen produced by these cells. The type X collagen molecules synthesized by the hypertrophic cells contained disulfide bonds within their triple-helical domains and assembled into a high-Mr aggregate. When polymerase chain reaction (PCR) was employed to amplify type X collagen sequences from cDNA obtained by reverse transcription of mRNA from cultures of both types of chondrocytes, only the hypertrophic chondrocyte mRNA yielded PCR amplification products indicative of the presence of type X collagen transcripts.

Amino Acid Sequence↗
PubMed1991

Characterization of a COL1A1 splicing defect in a case of Ehlers-Danlos syndrome type VII: further evidence of molecular homogeneity.

A child affected by the type VII form of Ehlers-Danlos syndrome (EDS VII) was shown to have a heterozygous structural defect in the amino-terminus of pro-alpha 1(I) collagen. As a result, type I procollagen trimers containing defective subunits are not converted to mature collagen molecules. To identify the cause of the protein abnormality, specifically primed cDNAs and genomic DNA were PCR amplified and sequenced. This analysis disclosed that the protein structural defect is caused by a single base substitution (A for G) at position -1 of the splice donor site of intron 6 of the pro-alpha 1(I) collagen gene (COL1A1). The affected allele produces (a) transcripts lacking exon 6 sequences and (b), in lesser amount, normally spliced transcripts. Furthermore, the rate of exon 6 skipping is temperature dependent, for it appears to decrease substantially when the patient's fibroblasts are incubated at 31 degrees C. These findings are similar to those we previously reported for other unrelated EDS VII cases and, therefore, reemphasize the molecular homogeneity of this rare connective tissue disorder.

Adult↗
PubMed1990

In vivo and in vitro noncovalent association of excised alpha 1 (I) amino-terminal propeptides with mutant pN alpha 2(I) collagen chains in native mutant collagen in a case of Ehlers-Danlos syndrome, type VII.

The cause of the Ehlers-Danlos syndrome Type VII (EDS VII) is considered to be defective removal of the amino-terminal propeptide (N-propeptide) of Type I procollagen due to deficiency of procollagen N-proteinase, the enzyme responsible for the normal proteolytic excision of this precursor-specific domain. Molecules retaining the N-propeptide (pN-collagen molecules) are thought to cause defective fibrillogenesis and cross-linking which eventuate in dramatic joint laxity and joint dislocations, the clinical hallmark of this variety of EDS. Recent studies demonstrate that some EDS VII patients harbor small deletions of either the pro-alpha 1(I) or pro-alpha 2(I) chain of Type I procollagen. We have found an 18-amino acid deletion (due to exon outsplicing) in a mutant pro-alpha 2(I) chain from such a patient. The deleted peptide is the junctional segment (N-telopeptide) linking the alpha 2(I) N-propeptide and major triple helical domains; loss of this short segment results in union of these latter domains and produces a shortened pN alpha 2(I) chain. Directly extracted tissue collagen and pepsin-digested fibroblast collagen contain this mutant pN alpha 2(I) chain and normal alpha 1(I) chains, but not pN alpha 1(I) chains, indicating that the relatively larger alpha 1(I) N-propeptide is excised from the related alpha 1(I) chains. The fate of this alpha 1(I) N-propeptide was unclear and therefore whether or not the intact N-propeptide was, in fact, retained in native mutant collagen was also unclear. In this paper, we describe morphologic, chemical, and immunochemical studies which indicate that the alpha 1(I) N-propeptide is retained in noncovalent association with the mutant pN alpha 2(I) chain in native mutant collagen molecules both in vivo and in vitro. In both instances, the alpha 1(I) N-propeptides are proteolytically cleaved from the related alpha 1(I) chains. These data suggest that retention of a partially cleaved, but essentially intact N-propeptide in mutant collagen may play a role in the pathogenesis of this disease.

Amino Acid Sequence↗