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PubMed1997

Alteromonas infernus sp. nov., a new polysaccharide-producing bacterium isolated from a deep-sea hydrothermal vent.

A deep-sea, aerobic, mesophilic and heterotrophic new bacterium was isolated from a sample of fluid collected among a dense population of Riftia pachyptila, in the vicinity of an active hydrothermal vent of the Southern depression of the Guaymas basin (Gulf of California). On the basis of phenotypic and phylogenetic analyses and DNA/DNA relatedness, the strain GY785 was recognized as a new species of the genus Alteromonas and the name of Alteromonas infernus is proposed. During the stationary phase in batch cultures in the presence of glucose, this bacterium secreted two unusual polysaccharides. The water-soluble exopolysaccharide-1 produced contained glucose, galactose, galacturonic and glucuronic acids as monosaccharides. The gel-forming exopolysaccharide-2 was separated from the bacterial cells by dialysis against distilled water and partially characterized.

Base Composition↗
PubMed2026

Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.

Focal cortical dysplasias (FCDs) are malformations of cortical development associated with drug-resistant focal epilepsy. We analyzed surgical tissue from 25 consecutive cases recruited from adult and pediatric epilepsy surgery programs. We performed high-depth sequencing of lesional tissue, validated somatic variants using droplet digital PCR or amplicon sequencing, and investigated genotype-phenotype correlations. A pathogenic or likely pathogenic variant was detected in 64% (n = 16/25) of cases. Of these, five cases with FCDIIa or FCDIIb had germline variants in NPRL3 (n = 3) or DEPDC5 (n = 2). Somatic variants were identified in 44% (n = 11/25) of cases. The genetic yield for FCDIIb was 77% of cases having a pathogenic mTOR pathway variant detected (n = 10/13), and for FCDIIa 66% (n = 6/9). High depth sequencing approaches allowed detection of somatic variants with very low (down to 0.4%) variant allele fractions (VAFs). No pathogenic variants were detected in 3 cases with FCDI. 62% (n = 15/24) of the cases with ≥12 months follow up experienced a favourable seizure outcome (Engel 1-2) following surgery. Of note, n = 9 patients required repeat surgery to resect residual dysplasia. Determining a genetic diagnosis reveals aetiology and paves the way to precision therapies that may benefit those with FCD who do not respond to current treatments.

Humans↗
PubMed2003

Morphologies and phylogenetic classification of cellulolytic myxobacteria.

The evolutionary distances of the 16S rDNA sequences in cellulolytic myxobacteria are less than 3%, which units all the strains into a single genus, Sorangium. The size of myxospores and the shape of sporangioles, rather than fruiting body colors or swarm morphologies are consistent with the changes of the 16S rDNA sequences. It is suggested that there are at least two species in the genus Sorangium: one includes strains with small myxospores and spherical sporangioles, and the color of the fruiting bodies is normally orange or brown, though sometimes yellow or black. The second species has large myxospores, polyhedral sporangioles with many inter-cystic substrates, and normally deep brown to black color.

Cellulose↗
PubMed2000

Marrow stromal cells embedded in alginate for repair of osteochondral defects.

Articular cartilage defects of sufficient size ultimately degenerate with time, leading to arthritic changes. Numerous strategies have been used to address full-thickness cartilage defects, yet none thus far has been successful in restoring the articular surface to its preinjury state. We compared the effects of agarose, alginate, and type I collagen gels on the expression of cartilage-specific markers from rabbit marrow stromal cells and then assessed the in vivo effects of cells seeded in alginate beads on the repair of full-thickness osteochondral defects in the rabbit model. Marrow aspirates from rabbits were cultured and the stromal population selected. Marrow stromal cells were then placed in either 1.2% w/v alginate, type I collagen gels (3 mg/mL), or 0.5% agarose suspension culture. After 2, 5, 10, and 20 days in culture, the RNA was extracted and analyzed by reverse transcription polymerase chain reaction for the cartilage-specific markers aggrecan and type II collagen. The strongest increase in aggrecan and type II collagen gene expression was found in the agarose suspension followed by alginate; type I collagen gels induced the lowest levels. Alginate beads were chondrogenic and maintained their size and consistency over time in culture, whereas the cell-seeded collagen gels invariably contracted. Full-thickness defects measuring 3 x 6 mm x 3 mm deep were then created in the medial femoral condyles of rabbit knees and filled with alginate beads, alginate beads seeded with stromal cells, or left empty. Alginate beads containing stromal cells remained within the defects and progressively filled the defects with regenerate tissue. Histologic analysis showed viable, phenotypically chondrogenic cells in the defects. The matrix stained positive with safranin O, indicating proteoglycan synthesis, and bonding between the regenerate and host tissue was excellent. We have shown quantitative differences in the chondrogenic effects of the biomaterials tested. Alginate induces the chondrogenic phenotype in marrow stromal cells in vitro, and possesses the necessary physical characteristics and handling properties to support cells and serve as a carrier to fill full-thickness osteochondral defects in vivo.

Alginates↗
PubMed2001

Isolation and identification of pathogenic strains of Streptomyces acidiscabies from netted scab lesions of potato tubers in Hokkaido (Japan).

A relatively homogeneous group of streptomycete isolates was obtained from netted scab lesions of potato tubers collected from a potato field in Hokkaido, Japan. Based on 55 phenotypic data of 72 Streptomyces strains selected from these isolated together with spectral data on their soluble pigments and with data of a PCR analysis, using species specific primers, these netted scab causing pathogenic organisms were identified as S. acidiscabies. S. acidiscabies had previously been isolated from deep (common) scab lesions in the USA and reported as thaxtomin A producer. In contrast, our S. acidiscabies strains were not able to induce deep scab symptoms on potato minitubers in pot test, did not produce the phytotoxin thaxtomin A and did not contain the pathogenicity related gene, nec-1.

Bacterial Proteins↗
PubMed2002

"Vanishing white matter" and ovarian dysgenesis in an infant with cerebro-oculo-facio-skeletal phenotype.

We describe a girl with intrauterine growth retardation, congenital cataracts, mild dysmorphic features and joint contractures. MRI performed at 1 week and 6 months, demonstrated postnatal cerebral and cerebellar atrophy and loss of white matter. The patient died at 10 months. Post-mortem examination revealed ovarian dysgenesis. There was normal development of neuronal and axonal structures, but lack of myelination in brainstem and cerebellum. Subcortical and deep white matter of the cerebral hemispheres were largely destroyed (cavitated), with preserved, but unmyelinated axons in other brain areas. These findings are compatible with a severe leukodystrophic process of pre- or perinatal onset. The exact pathogenesis is not known.

Abnormalities, Multiple↗
PubMed1978

Genetic aspects of intracellular motility: cortical localization and insertion of trichocysts in Paramecium tetraurelia.

Wild-type and selected mutants of Paramecium tetraurelia were subjected to detailed analysis of the trichocyst phenotype. The characteristics of morphology, saltatory motility, and cortical insertion of trichocysts were found to be genetically distinguishable. In mutants with defective trichocyst saltatory motility, other intracellular motility systems (i.e. mitochondrial saltatory motility, and cyclosis) appeared to be unaffected. Saltatory motility appears to be an essential intermediate step in the functional development of the trichocyst, since it serves to transport the trichocyst from its site of assembly, deep in the cytoplasm, to the cortex, where it is inserted and becomes discharge-competent. If trichocyst saltatory motility is lost, as in the mutants ndA and tam8, then trichocysts are not transported to the cortex and are therefore not inserted. However, the successful transport of a trichocyst to the cortex does not guarantee the proper insertion of that trichocyst, as in the case of the mutant am. Apparently there are independent steps involved specifically with trichocyst insertion. The gross morphology of the trichocyst appears to be independent of its saltatory motility, and to a degree, independent of cortical insertion.

Animals↗
PubMed2000

[Functional results after surgical extraction or photocoagulation of choroid neovascularization (CNV) in age-related macular degeneration].

BACKGROUND: SLO microperimetric examination after the extraction of choroidal neovascular membranes (CNV) in age-related macular degeneration (AMD) shows absolute scotoma in the area of pigment epithelial loss. Laser treatment also causes complete functional loss. The functional results of these two methods should be compared before the surgical procedure is expanded. METHODS AND PATIENTS: Five eyes of five patients with large subfoveal well-defined CNV were treated by photocoagulation following the MPS criteria. Functional results were compared with similar phenotypes from a group of 78 patients operated upon. Before and after the treatment visual acuity was tested following the ETDRS criteria. The need for magnification for reading was tested using the ZEISS charts. Fundus-controlled microperimetry was performed using the scanning laser ophthalmoscope (Rodenstock) to detect deep and relative scotomata. RESULTS: The recurrence rate (OP 2/5; ALK 1/5) was normal regarding the small number of patients. Visual results are slightly better in patients operated on (mean: pre 0.08; 6 weeks 0.09; 3 month 0.13; last 0.13) than in laser-treated patients (mean: pre 0.06; 6 weeks 0.07; 3 months 0.08; last 0.12). Deep scotoma can be reduced with surgical extraction of the CNV (mean factor: 6 weeks 0.6; last control 0.8) while laser treatment of the margins enlarges the scotoma (mean factor: 6 weeks 2.3; last control 2.2). CONCLUSIONS: Because of the minimal functional advantages of the surgical procedure we do not think it is the method of first choice. For both methods the treatment of well-defined CNV increases the possibility of low-vision rehabilitation.

Age Factors↗
PubMed1997

Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy.

OBJECTIVE: Our purpose was to evaluate activated protein C resistance phenotype and genotype among patients with thrombosis during pregnancy and the puerperium. STUDY DESIGN: This observational study was conducted prospectively during a 2-year period (July 1993 to June 1995) in a preselected population. All patients admitted to our high-risk pregnancy unit with a diagnosis of deep vein thrombosis, pulmonary emboli, transient ischemic attack, and cerebrovascular accident during pregnancy and the puerperium were included. Prothrombin time, partial thromboplastin time, fibrinogen levels, protein C, protein S, antithrombin III, functional test for activated protein C resistance, and factor V Leiden mutation by polymerase chain reaction were performed on each patient. RESULTS: Fifteen patients were included. Seven (46.6%) patients were positive for activated protein C resistance (factor V Leiden). All other coagulation studies were negative for all patients. All patients with activated protein C resistance had a venous thrombotic event, deep vein thrombosis, or pulmonary emboli, and only one had a cerebrovascular accident on the basis of sagittal sinus thrombosis. Only two of the activated protein C resistance-negative patients had venous thrombosis (pulmonary emboli). The remaining six patients had transient ischemic attacks or cerebrovascular accidents. For the subgroup with venous thrombosis during pregnancy and the puerperium, the incidence of activated protein C resistance (factor V Leiden) was 78%. CONCLUSION: This study demonstrates the incidence of factor V Leiden in a selected population in whom thrombotic events developed during pregnancy and the puerperium. This small-scale study provides justification for a large cohort study that will identify women with factor V Leiden and determine their risk for thrombosis during pregnancy and the puerperium. We believe that factor V Leiden should be evaluated in conjunction with thrombotic events in the pregnant woman.

Adult↗
PubMed2002

Dynamics of telomeric DNA turnover in yeast.

Telomerase adds telomeric DNA repeats to telomeric termini using a sequence within its RNA subunit as a template. We characterized two mutations in the Kluyveromyces lactis telomerase RNA gene (TER1) template. Each initially produced normally regulated telomeres. One mutation, ter1-AA, had a cryptic defect in length regulation that was apparent only if the mutant gene was transformed into a TER1 deletion strain to permit extensive replacement of basal wild-type repeats with mutant repeats. This mutant differs from previously studied delayed elongation mutants in a number of properties. The second mutation, TER1-Bcl, which generates a BclI restriction site in newly synthesized telomeric repeats, was indistinguishable from wild type in all phenotypes assayed: cell growth, telomere length, and in vivo telomerase fidelity. TER1-Bcl cells demonstrated that the outer halves of the telomeric repeat tracts turn over within a few hundred cell divisions, while the innermost few repeats typically resisted turnover for at least 3000 cell divisions. Similarly deep but incomplete turnover was also observed in two other TER1 template mutants with highly elongated telomeres. These results indicate that most DNA turnover in functionally normal telomeres is due to gradual replicative sequence loss and additions by telomerase but that there are other processes that also contribute to turnover.

DNA, Fungal↗
PubMed2025

Convergent latitudinal erosion of circadian systems in a rapidly diversifying order of fishes.

Biological clocks enable organisms to anticipate cyclical environmental changes. Some habitats, such as those at high latitudes or deep sea, experience seasonally diminished or absent diel cues upon which species entrain their circadian rhythms. Fishes of the order Perciformes have rapidly diversified and adapted to these arrhythmic ecosystems, raising the possibility that evolutionary modifications to their circadian biology contributes to their success as one of the most species-rich orders of vertebrates. Here, we used a comparative genomic approach to investigate patterns of biological clock gene loss and circadian rhythms across 33 perciform and six outgroup species. We found both widespread and lineage-specific loss and relaxed selection in core clock genes, particularly in the convergently evolving polar and deep-sea Notothenioidei and Cottioidei suborders. This trend of circadian gene loss was significantly correlated with latitude, with higher-latitude species showing greater loss. Whether these losses and relaxed selection lead to changes in circadian rhythms is unknown for most perciforms. To address this, we performed metabolic phenotyping on three notothenioid species and found no circadian metabolic oscillations during the late austral fall, including in the sub-Antarctic Eleginops maclovinus, sister to the Antarctic adaptive radiation. We propose that diminished reliance on endogenous biological clocks may be an adaptive feature that facilitates the survival and diversification of perciform fishes in polar and arrhythmic environments.

Journal Article↗
PubMed1995

Differential expression of collagen types I, II, III, and X in human osteophytes.

BACKGROUND: Osteophytes are neoplastic cartilaginous and osseous protrusions growing at the margins of osteoarthritic joints. Their formation involves complex patterns of cellular proliferation, differentiation, as well as matrix synthesis and turnover that are poorly understood. EXPERIMENTAL DESIGN: Here we report on an experimental approach using in situ hybridization and immunohistology to elucidate pathways of chrondrocyte differentiation in human osteophytes. Ab and cDNA probes for collagen types were used as specific parameters for chondrocyte phenotypes. RESULTS: In early precartilaginous mesenchymal tissue, cytoplasmic mRNA for alpha 1(I) and alpha 1(III) collagen genes (Col1A1 and Col3A1) were found by in situ hybridization, correlating with the distribution of type I and III collagen as revealed by Ab staining. Strong expression of type II collagen both at mRNA and protein levels was the hallmark of chondrogenic differentiation in the cartilaginous zone of osteophytes. Type II collagen expression increased in all cartilaginous and fibrocartilaginous areas with growth and maturation of osteophytes. The signal intensity obtained after in situ hybridization with a COL2A1 probe was high and corresponded to that obtained in fetal cartilage, whereas normal adult articular cartilage usually did not show measurable type II collagen expression. In fibrocartilaginous areas, the most abundant, but heterogeneous tissue type seen in osteophytes, type II and III collagen mRNA expression overlapped considerably. Type III collagen was scattered, both pericellularly and interterritorially, over the whole osteophyte, excluding bone and chondrocytic cells of the deep zone. The strongest type I collagen expression was seen in bone and in the superficial fibrous layer. In areas of endochondral ossification, large chondrocytes were found expressing type X collagen, a specific marker for hypertrophic chondrocytes. CONCLUSIONS: These results show that discrete stages of cartilage differentiation can be precisely followed in osteophytes using collagen type-specific cDNA probes and Ab as markers. In addition, a fibrocartilaginous chondrocyte phenotype was identified that expresses type II and III, but not type I collagen.

Aged↗
PubMed1992

Cellular repopulation of deep-frozen meniscal autografts: an experimental study in the dog.

This study evaluated the cellular repopulation of deep-frozen meniscal autografts. Medial menisci of adult dogs were excised, deep-frozen in liquid nitrogen (-196 degrees C) for 10 min, and orthotopically reimplanted into the joint. Deep-freezing was found to effectively kill all the cells within the meniscus as determined by the absence of Na(2)35SO4 incorporation. Following orthotopic replacement within the knee joint, menisci were repopulated with cells that seemed to originate from the adjacent synovium. These cells migrated over the surface of the meniscus and began to invade the deeper layers of the tissue. However, even after 6 months, the central core of the meniscus remained acellular. While the new cells appeared to modulate into cells that are similar in appearance to meniscal fibrochondrocytes, the exact phenotypic expression of these newly differentiated cells has yet to be determined. Histological alterations, as manifested by a loss of normal orientation of the collagen architecture of the superficial layers of the meniscus; was evident at 6 months and suggests that a remodeling phenomenon may be associated with the cellular repopulation. While biomaterial studies have not been carried out on these specimens, the morphologic alterations observed in the collagen orientation would suggest a possible alteration in the material properties of the repopulated meniscus. The clinical implication of this study is that the structural remodeling associated with the cellular repopulation of deep-frozen meniscal allografts may make the transplanted meniscus more susceptible to injury.

Animals↗
PubMed1975

The 12p trisomy syndrome.

Trisomy for the short arm of chromosome number 12 was diagnosed (by a G-banding method) in a girl with multiple congenital defects. Her mother and two sisters showed a balanced translocation 46,XX,rcp(12;21)(p11;p11), so, the affected girl was the result of a maternal adjacen t-1 meiotic segregation with a karyotype 46,XX,der21,rcp(12;12)(p11;q11)mat. Another sister decreased at 3 yr of age showed similar phenotypical features and was considered also affected although no karyotype studies were performed. Both affected cases were compared with a previous one and the concordant characteristics allowed the individualization of the following syndrome: severe mental retardation, peculiar flat facies with prominent checks, epicanthic folds, broad and irregular implantation of the eyebrows, broad and flat nasal bridge with short and narrow nose, anteverted nostrils and large philtrum, broad and prominent lower lip, low set ears with folded helix, prominent anthelix and deep concha, "spade" shape fingers (sharp-pointed distal phalanges) with shortness of the fifth, bilateral genu valgum, slightly increased space between first and second toes, secral dimple, generalized hypotonia and hyporeflexia of knees and ankles, nistagmus, retarded and dysrythmic bone age, simian creases or equivalent and distal axial triradii.

Abnormalities, Multiple↗
PubMed1993

[Some problems on the clinical phenotype of Machado-Joseph disease in relation between their ages at onset].

UNLABELLED: This study proposed that three phenotypes of Machado-Joseph disease (MJD) are closely related to the patients' ages at onset. MATERIALS: Six patients from two families. Autopsy performed in three of them (case 2, 4, 5). Two patients are a father (case 4) and his son (case 5). RESULTS: 1. Clinical features. All cases showed cerebellar ataxia and nystagmus. Progressive nuclear oculomotor palsy was common except for one case who killed himself in the early clinical stage. Pyramidal symptom which is increased deep tendon reflexes, spasticity, and extesor plantar response was common for three patients (case 3, 5, 6) whose ages of onset are under 40 years. One case (case 5) developed dystonia of foot at the age of ten and he developed the symptom of type 1 of MJD. However, the other three patients (case 1, 2, 4) who developed ataxia after the middle of the fifth decade showed hypotonia and decreased or absence of deep tendon reflexes from the beginning. The latter did not revealed spasticity or dystonia. Their clinical symptoms were identical with the type 3 of MJD. In spite of ages at onset, they showed general muscular atrophy and sensory disturbance in the advanced clinical course. 2. Neuropathological findings. 1) cerebellar system: Severe degeneration in the spinocerebellar system and mild to moderate one in the pontocerebellar system and dentate nuclei. The inferior olivary nucleus and the cerebellar cortex were almost preserved. 2) extrapyramidal system: Moderate to severe degeneration in the substantia nigra, globus pallidus (prominent in the internal segment) and subthalamic nucleus. 3) Degeneration in the oculomotor nuclei, motor neurons in the anterior horn and dorsal column of the spinal cord. CONCLUSION: These clinico-pathological findings indicate the difference of clinical phenotype is not always reflected those of neuropathological findings. The review of our experience and the literature suggests that the clinical features of MJD symptoms are related to the patients' ages at onset and clinical progression of the disease. When the disease begins before the age of ten, dystonia is an initial symptom, followed by pyramidal symptoms and cerebellar ataxia (type 1). In the early adult cases, the onset in which is earlier than forty, cerebellar ataxia and pyramidal symptoms are the initial symptoms, followed by extrapyramidal symptoms such as dystonia or choreoathetoid movements or both (type 2). In both instances however, decreased DTRs, muscular atrophy and sensory disturbance are common clinical manifestations at the advanced clinical stage. In late adult MJD cases with the age at onset after forty, the initial symptom is progressive cerebellar ataxia with hypotonia, followed by muscular atrophy and sensory disturbance (type 3). In spite of a marked degeneration in the extrapyramidal system, few or no extrapyramidal symptoms are detected in the last cases.

Adult↗
PubMed2025

Deep immune profiling of intrahepatic cholangiocarcinoma with CODEX multiplexed imaging.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) may be genomically subclassified by the presence of potentially actionable molecular aberrations, of which pathogenic alterations in isocitrate dehydrogenase (IDH)1 and fibroblast growth factor receptor (FGFR)2 are the most frequently observed. The impact of these molecular alterations on the tumor immune microenvironment remains incompletely understood. METHODS: We performed a high-parameter spatial immune phenotyping of iCCA samples with pathogenic FGFR2 or IDH1 alterations and FGFR2/IDH1 wild-type controls at the single-cell level using CO-Detection by indEXing. RESULTS: A total of 24 tumors were examined. Tumors with FGFR2 alterations were characterized by fewer CD8+ T cells and "M2-like" macrophages but higher levels of polymorphonuclear myeloid-derived suppressor cells as compared to FGFR2 wild-type tumors. Spatial relationships between polymorphonuclear myeloid-derived suppressor cells and multiple other cell types in the tumor microenvironment (including tumor cells, CD4+, and CD8+ T cells) were enriched in tumors with FGFR2 alterations. Tumors with IDH1 mutations had a trend toward more fibroblasts and were characterized by a closer proximity of tumor cells to CD4+ T cells, and between macrophages and multiple structural tumor microenvironment components as compared to other subtypes. CONCLUSIONS: iCCAs with pathogenic FGFR2 fusions/rearrangements and IDH1 mutations have distinct immunophenotypes. Tailoring immunotherapeutic approaches to specific molecular subsets could improve treatment outcomes across the divergent molecularly defined iCCA subtypes.

Humans↗
PubMed2004

Recent insights in the development of organ damage caused by hypertension.

Recent recommendations for the management of hypertension have stressed the importance of assessing subclinical target organ damage for the evaluation of cardiovascular risk, the choice of antihypertensive treatment and the follow-up of hypertensive patients. In addition to classic hallmarks of target organ damage (left ventricular hypertrophy, renal dysfunction, microalbuminuria), new concepts emerging from basic research and technical progresses have allowed more accurate and earlier detection of target organ damage affecting the heart (plasma BNP, coronary calcifications), the brain (silent lacunar infarcts, advanced deep white matter lesions, microbleedings) and the vasculature. The latter include markers of diffuse atherosclerosis (carotid intima-media thickness), arterial stiffness (pulse wave velocity, augmentation index) and endothelial dysfunction (increased plasma levels of adhesion molecules). Current studies should help to better define the predictive power of these new phenotypes for the occurrence of overt cardio- and cerebrovascular diseases, their reversibility under antihypertensive treatment and the most adapted therapeutic strategy in at-risk patients. Furthermore, early identification of hypertensive patients more likely to develop target organ damage, will be facilitated by a more global evaluation of cardiovascular risk factors, a better use and wider acceptance of ambulatory BP measurement (including determination of nocturnal dip and blood pressure variability) and, maybe, an increased knowledge of the genetic factors underlying susceptibility to target organ damage. Lastly, randomized studies comparing different classes of antihypertensive drugs should help to test the well-known but frequently challenged concept of additional benefits of some antihypertensive drugs "beyond BP" on prevention and reversal of target organ damage.

Antihypertensive Agents↗
PubMed1992

Chondrodysplasia in transgenic mice harboring a 15-amino acid deletion in the triple helical domain of pro alpha 1(II) collagen chain.

We have generated transgenic mice by microinjection of a 39-kb mouse pro alpha 1(II) collagen gene construct containing a deletion of exon 7 and intron 7. This mutation was expected to disturb the assembly and processing of the homotrimeric type II collagen molecule in cartilage. Expression of transgene mRNA at levels equivalent or higher than the endogenous mRNA in the offspring of two founder animals resulted in a severe chondrodysplastic phenotype with short limbs, hypoplastic thorax, abnormal craniofacial development, and other skeletal deformities. The affected pups died at birth due to respiratory distress. Light microscopy of epiphyseal growth plates of transgenic pups demonstrated a marked reduction in cartilaginous extracellular matrix and disruption of the normal organization of the growth plate. The zone of proliferating chondrocytes was greatly reduced whereas the zone of hypertrophic chondrocytes was markedly increased extending deep into the diaphysis suggestive of a defect in endochondral ossification. Electron microscopic examination revealed chondrocytes with extended RER, a very severe reduction in the amount of cartilage collagen fibrils, and abnormalities in their structure. We postulate that the deletion in the alpha 1(II) collagen acts as a dominant negative mutation disrupting the assembly and secretion of type II collagen molecules. The consequences of the mutation include interference with normal endochondral ossification. These mice constitute a valuable model to study the mechanisms underlying human chondrodysplasias and normal bone formation.

Animals↗