Atelosteogenesis type II (AO II) is a neonatally lethal chondrodysplasia whose clinical and histological characteristics resemble those of another chondrodysplasia, the much less severe diastrophic dysplasia (DTD). The similarity suggests a shared pathogenesis involving lesions in the same biochemical pathway and perhaps the same gene. DTD is caused by mutations in the recently identified diastrophic dysplasia sulfate-transporter gene (DTDST). Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro. Together with our recent observation that a third even more severe chondrodysplasia, achondrogenesis type IB, is also caused by mutations in DTDST, these results demonstrate a phenotypic series of three chondrodysplasias of increasing severity caused by lesions in a single sulfate-transporter gene. The severity of the phenotype appears to be correlated with the predicted effect of the mutations on the residual activity of the DTDST protein.

Anion Transport Proteins↗

PubMed1995

Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3.

Thanatophoric dysplasia (TD), the most common neonatal lethal skeletal dysplasia, affects one out of 20,000 live births. Affected individuals display features similar to those seen in homozygous achondroplasia. Mutations causing achondroplasia are in FGFR3, suggesting that mutations in this gene may cause TD. A sporadic mutation causing a Lys650Glu change in the tyrosine kinase domain of FGFR3 was found in 16 of 16 individuals with one type of TD. Of 39 individuals with a second type of TD, 22 had a mutation causing an Arg248Cys change and one had a Ser371Cys substitution, both in the extracellular region of the protein. None of these mutations were found in 50 controls showing that mutations affecting different functional domains of FGFR3 cause different forms of this lethal disorder.

Alleles↗

PubMed1995

A radiographic, morphologic, biochemical and molecular analysis of a case of achondrogenesis type II resulting from substitution for a glycine residue (Gly691-->Arg) in the type II collagen trimer.

The type II collagenopathies form a continuous spectrum of clinical severity, ranging from lethal achondrogenesis type II and hypochondrogenesis, through spondyloepiphyseal dysplasia, spondyloepimetaphyseal dysplasia and Kniest dysplasia to the Stickler syndrome and familial precocious osteoarthropathy at the mildest end of the spectrum. We have carried out a radiographic, morphologic, biochemical and molecular study in a case of achondrogenesis type II. Electron micrographs showed inclusion bodies of dilated rough endoplasmic reticulum in the chondrocytes and the presence of sparse collagen fibers in the cartilage matrix. Protein analysis of collagen from cartilage indicated posttranslational overmodification of the major cyanogen bromide peptides, and suggested a mutation near the carboxyl terminus of the type II collagen molecule. Analysis at the DNA level demonstrated that the phenotype was produced by a single base change (G-->C) that resulted in the substitution of glycine691 by arginine in the type II collagen triple helical domain. We confirm previous observations in three cases of hypochondrogenesis that glycine substitutions in the alpha 1(II) chain can result in a phenotype at the most severe end of the type II collagenopathy spectrum.

Abortion, Induced↗

PubMed1994

Expression, in cartilage, of a 7-amino-acid deletion in type II collagen from two unrelated individuals with Kniest dysplasia.

Kniest dysplasia is a heritable chondrodysplasia that severely affects skeletal growth. Recent evidence suggests that the etiology is based on mutations in COL2A1, the gene for collagen type II. We report the detection and partial characterization of an identical defect in type II collagen in two unrelated patients with Kniest dysplasia. Analysis of cyanogen bromide (CB)-digested cartilage samples from both probands by SDS-PAGE revealed an abnormal band for peptide alpha 1(II)CB12. The peptide was purified and digested with endoproteinase Asp-N. Fragments unique to the Kniest tissues were identified by reverse-phase high-pressure liquid chromatography and by sequence analysis. The results established a deletion of amino acids 102-108 of the alpha 1(II) triple-helical domain, which disrupted the (gly-X-Y)n repeat needed for helix formation. This was confirmed by sequence analysis of DNA amplified from both probands, revealing the molecular basis to be a single nucleotide mutation at a CpG dinucleotide (GCG-->GTG) in the codon for alanine 102. The mutation created a new splice donor site, which would account for the absence of the last seven amino acids from the 3' end of exon 12 in alpha 1(II)CB12. Light and electron micrographs of the probands' cartilage showed the perilacunar foamy matrix ("Swiss cheese") characteristic of Kniest dysplasia and chondrocytes containing dilated rough endoplasmic reticulum, which earlier studies had shown were filled with type II procollagen. These two cases strengthen the concept that Kniest dysplasia is based on mutations of COL2A1 and belongs within the broad spectrum of chondrodysplasias caused by type II collagenopathies.

Adult↗

PubMed1989

Reduced fetal platelet counts in pregnancies with abnormal Doppler umbilical flow waveforms.

Fetal and maternal platelet counts were correlated with antenatal assessment of the umbilical-placental waveform. Forty singleton pregnancies were studied using Doppler ultrasound, and placental resistance was categorized as normal or high according to the systolic/diastolic ratio. We performed platelet counts on maternal and cord blood taken at the time of cesarean section. The high-resistance group had a mean fetal platelet count (218 +/- 53 x 10(3)/microliters) significantly lower than that of the normal-resistance group (314 +/- 76 x 10(3)/microliters) (P less than .001). This difference was evident in both the hypertensive and nonhypertensive subgroups of the high-resistance group. There was no difference in mean maternal platelet counts between the high- and normal-resistance groups.

Adult↗

PubMed1981

The effect of lead upon urate nucleation.

Lead urate was crystallized from solutions originally containing 0.595 mM (10 mg%) urate and 0.297 mM PbCl2. In the absence of lead, monosodium urate does not nucleate unless the urate concentration exceeds 80 mg%. Lead urate crystals were negatively birefringent and had a distinct x-ray powder diffraction pattern. Crystals of monosodium urate nucleated on lead urate seed crystals when the urate concentration was 10 mg%. These studies indicate that with physiologic conditions of temperature, pH, and ionic strength, spontaneous nucleation of lead urate can be demonstrated.

Chemical Phenomena↗

PubMed1980

Studies on the nucleation of monosodium urate at 37 degrees c.

Factors influencing the nucleation of monosodium urate (NaHU) were studied with supersaturated solutions of sodium urate at physiologic conditions of temperature, pH, and ionic strength. Spontaneous nucleation of NaHU did not occur at urate concentrations of 5 mM (84 mg%) in the presence of 140 mM Na ion. Addition of synovial fluids from gout patients greatly enhanced nucleation, whereas fluids from degenerative joint disease patients moderately enhanced nucleation, and fluids from rheumatoid arthritis patients had only a slight effect. Hyaluronic acid and purines minimally enhanced urate crystallization, whereas other connective tissue components had no effect.

Connective Tissue↗

PubMed1975

Nucleation of monosodium urate crystals.

(1) Calcium greatly increased crystallization of monosodium urate in otherwise pure water, by enhancing both nucleation and growth. (2) Acid accelerated urate nucleation, both by its direct action and indirectly by increasing the free calcium in physiological fluids. (3) Synovial fluid from one gouty patient accelerated urate nucleation, while that from one rheumatoid patient inhibited nucleation. (4) X-rays, collagen, ethyl alcohol, cupric ion, and potassium ion all had negligible influence on urate nucleation. (5) Mechanical shock greatly increased urate nucleation.

Acid-Base Equilibrium↗

PubMed1974

Factors affecting urate solubility in vitro.

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Blood↗

PubMed1972

Solubility of uric acid and monosodium urate.

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Crystallization↗

PubMedDate not supplied

Electron microscopical study in multiple epiphyseal dysplasia type II.

An electron microscopic examination of articular cartilage of two cases with multiple epiphyseal dysplasia type II was performed. The cartilage had a normal cell distribution and no signs of gross degeneration were found. Chondrocytes showed normal ultrastructural characteristics without dilation of the rough endoplasmic reticulum. The matrix contained normal banded collagen fibrils, proteoglycans, and aggregated fibrils.

Adolescent↗