A rare cause of short stature: Leri Weill dyschondrosteosis

Short stature is a common pediatric problem. It may occur rarely as a result of genetic disorders. Leri-Weill dyschondrosteosis (LWD) is one of the rare genetic disorders of skeletal system resulting with short stature. It is characterized by shortness of stature and Madelung deformity of the wrist. Here we report a case of LWD with some skeletal stigmas of Turner syndrome. She has also depressed medial tibial condyles that to our knowledge, has not previously been reported in LWD.     

Identification of the sea urchin 350-kDa sperm-binding protein as a new sialic acid-binding lectin that belongs to the heat shock protein 110 family: implication of its binding to gangliosides in sperm lipid rafts in fertilization

The 350-kDa sperm-binding protein (SBP), a species-specific sperm-binding protein, is localized in the vitelline layer of sea urchin eggs. In this study, we have shown for the first time that sperm gangliosides are ligands for the intact glycosylated SBP. Using recombinant fragments of the SBP, the N-terminal heat shock protein 110-like domain was shown to be responsible for the binding. The intact SBP could bind various gangliosides, and the binding was sialidase-sensitive and inhibited by sialyllactose, thus indicating that it is the sialic acid-binding protein. Calcium and magnesium ions were not required but they did enhance the binding activity of SBP. The observation that bacterially expressed recombinant SBP and the sialidase-treated intact glycosylated SBP lost divalent cation-dependent enhancement of binding activity suggests that the sialylated carbohydrate moieties of the SBP may be involved in this property. Furthermore, the SBP was shown to bind sperm lipid rafts, in which gangliosides are enriched, and this binding was lost upon sialidase treatment of the lipid rafts. Finally, liposomes containing the ganglioside specifically inhibited fertilization. Taken together, these results allow us to identify SBP as a member of a new class of sialic acid-binding lectin belonging to the Hsp110 family, and indicate that SBP may be involved in interaction of sperm with the vitelline layer of the egg.     

Contractile responses of the human umbilical artery to KCl and serotonin in Ca-free medium and the effects of levcromakalim

It is known that K(ATP) channel openers inhibit the release and refilling of Ca(2+) from intracellular stores. The present study was designed to test the effects of levcromakalim in human umbilical artery (HUA) rings stimulated by serotonin (5-HT) and KCl in Ca-free medium. Umbilical cords were obtained at vaginal or cesarean deliveries from healthy, term pregnancies. After the isolation, HUA rings were placed in organ baths in solution with indomethacin (10(-5) M) and N(G)-nitro-L-arginine methyl ester (L-NAME) (10(-3) M) at 37 degrees C and aerated with 95% O(2) and 5% CO(2) for the measurement of isometric force. In Ca-free solution with Ethylene glycol-bis (ss-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) (2 mM) the contractions produced by 5-HT (10(-6) M) and KCl (40 mM) decreased significantly. Afterwards, HUA rings were treated with 5-HT and KCl in repeated manner in Ca-free medium. In contrast to KCl, 5-HT induced contractions reduced in each application, progressively. Levcromakalim (10(-4) M) abolished the contractions elicited by 5-HT. On the other hand, levcromakalim had a little but significant inhibitory effect on KCl induced contraction in Ca-free medium. These results suggest that Ca(2+) is not the only transduction pathway in KCl produced contractions of HUA smooth muscle cells.     

DNA damage and antioxidant defense in peripheral leukocytes of patients with Type I diabetes mellitus

We determined relationship among DNA damage, nitric oxide (NO) and antioxidant defense in leukocytes of patients with Type 1 DM. DNA damage was evaluated as strand breakage and formamidopyrimidine DNA glycosylase (Fpg)-sensitive sites by the comet assay in DNA from leukocytes of the subjects. Nitrite level, as a product of NO, superoxide dismutase (SOD) activity and glutathione peroxidase (G-Px) activity of the leukocytes were measured by spectrophotometric kits. Serum glucose level and glycosylated haemoglobin (HbA(1c)) were higher in the patients, as expected. Differences in measured parameters between controls and patients were assessed in men and women separately. There was no significant difference between patient and control groups in neither men nor women for nitrite level. Strand breakage and Fpg-sensitive sites were found to be increased, SOD and G-Px activities of the leukocytes were found to be decreased in both men and women of patient group as compared to their respective controls. Significant correlations were determined between strand breakage and HbA(1c) (r = 0.37, P<0.05); Fpg-sensitive sites and HbA(1c) (r = 0.59, P<0.01); Fpg-sensitive sites and glucose (r = 0.45, P<0.02); Fpg-sensitive sites and SOD (r = -0.48, P<0.02); HbA(1c) and SOD (r = -0.50, P<0.02). In conclusion, impaired antioxidant defense in leukocytes of patients with Type 1 DM may be one of the responsible mechanisms for increased DNA damage in those patients.     

Gramicidin A channel as a test ground for molecular dynamics force fields

We use the well-known structural and functional properties of the gramicidin A channel to test the appropriateness of force fields commonly used in molecular dynamics (MD) simulations of ion channels. For this purpose, the high-resolution structure of the gramicidin A dimer is embedded in a dimyristoylphosphatidylcholine bilayer, and the potential of mean force of a K(+) ion is calculated along the channel axis using the umbrella sampling method. Calculations are performed using two of the most common force fields in MD simulations: CHARMM and GROMACS. Both force fields lead to large central barriers for K(+) ion permeation, that are substantially higher than those deduced from the physiological data by inverse methods. In long MD simulations lasting over 60 ns, several ions are observed to enter the binding site but none of them crossed the channel despite the presence of a large driving field. The present results, taken together with many earlier studies, highlights the shortcomings of the standard force fields used in MD simulations of ion channels and calls for construction of more appropriate force fields for this purpose.     

Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia

Perlecan, a large heparan sulfate proteoglycan, is a component of the basement membrane and other extracellular matrices and has been implicated in multiple biological functions. Mutations in the perlecan gene (HSPG2) cause two classes of skeletal disorders: the relatively mild Schwartz-Jampel syndrome (SJS) and severe neonatal lethal dyssegmental dysplasia, Silverman-Handmaker type (DDSH). SJS is an autosomal recessive skeletal dysplasia characterized by varying degrees of myotonia and chondrodysplasia, and patients with SJS survive. The molecular mechanism underlying the chondrodystrophic myotonia phenotype of SJS is unknown. In the present report, we identify five different mutations that resulted in various forms of perlecan in three unrelated patients with SJS. Heterozygous mutations in two patients with SJS either produced truncated perlecan that lacked domain V or significantly reduced levels of wild-type perlecan. The third patient had a homozygous 7-kb deletion that resulted in reduced amounts of nearly full-length perlecan. Unlike DDSH, the SJS mutations result in different forms of perlecan in reduced levels that are secreted to the extracellular matrix and are likely partially functional. These findings suggest that perlecan has an important role in neuromuscular function and cartilage formation, and they define the molecular basis involved in the difference in the phenotypic severity between DDSH and SJS.