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H Yang

Publications and source records attributed to H Yang.

At least 19 recordsLinked to original sources
PubMed2000

Bootstrap confidence intervals for the sensitivity of a quantitative diagnostic test.

We examine bootstrap approaches to the analysis of the sensitivity of quantitative diagnostic test data. Methods exist for inference concerning the sensitivity of one or more tests for fixed levels of specificity, taking into account the variability in the sensitivity due to variability in the test values for normal subjects. However, parametric methods do not adequately account for error, particularly when the data are non-normally distributed, and non-parametric methods have low power. We implement bootstrap methods for confidence limits for the sensitivity of a test for a fixed specificity and demonstrate that under certain circumstances the bootstrap method gives more accurate confidence intervals than do other methods, while it performs at least as well as other methods in many standard situations.

Algorithms↗
PubMed2000

In vitro evaluation of hepatitis B virus polymerase mutations associated with famciclovir resistance.

Several mutations (V521L, P525L, L528M, T532S, and V555I) in the gene for hepatitis B virus (HBV) polymerase have been identified in HBV isolated from patients that displayed break-through viremia during famciclovir treatment. To determine whether these mutations cause phenotypic resistance to famciclovir, we compared the inhibition constants (K(i)) of penciclovir triphosphate (PCVTP, the active metabolite of famciclovir) for recombinant wild-type and mutant HBV polymerases containing these mutations. In in vitro enzymatic assays, the V555I mutation displayed the most resistance (with K(i) increased by 6.2-fold) to PCVTP. The V521L and L528M mutations showed moderately decreased sensitivity to PCVTP (K(i) increased by >3-fold). We also analyzed the cross-resistance profiles of these variants for adefovir and lamivudine, two other antiviral agents that also inhibit DNA replication by HBV polymerase. All 5 famciclovir-associated mutations were sensitive to adefovir diphosphate (ADVDP) in in vitro enzymatic assays (<2.3-fold decreased sensitivity). The V521L, L528M, and T532S mutations were also sensitive to lamivudine triphosphate (LAMTP); however, the P525L and V555I mutations displayed moderately decreased sensitivity to LAMTP in enzymatic assays (3.6-fold decreased sensitivity). The lamivudine-resistant mutations M552I, M552V, and L528M+M552V, which were previously shown to display 8- to 25-fold resistance to LAMTP, were less resistant (< or = 3.1-fold) to PCVTP.

2-Aminopurine↗
PubMed2000

Activation of the parapyramidal region in the ventral medulla stimulates gastric acid secretion through vagal pathways in rats.

Neurons synthesizing thyrotropin-releasing hormone, substance P and serotonin in the medullary caudal raphe nuclei project to the dorsal vagal complex and play a role in the central vagal regulation of gastric function. Neurons in the parapyramidal region in the ventral medulla share similar biochemical coding and projections as those in the caudal raphe nuclei. The role of the parapyramidal region in the autonomic regulation of gastric acid secretion was investigated in urethane-anesthetized rats. Unilateral microinjection of kainate into the parapyramidal region at 10, 15 and 20 ng induced a dose-related stimulation of gastric acid secretion (net increases: 22.2+/-11.2, 40.5+/-8.5 and 89.8+/-19.4 micromol/60 min, respectively), while injection of vehicle had no effect (net change: -0.1+/-1.4 micromol/60 min). Time-course studies showed a nine-fold peak increase over basal at 30 min after parapyramidal injection of kainate (20 ng) and acid secretion returned to basal level at 70 min. Microinjections of kainate (15-20 ng) outside the parapyramidal region or into the parapyramidal region in vagotomized rats had no effect. Exposure to cold (4 degrees C) for 2 h, which is known to induce vagally mediated gastric secretory and motor responses through medullary thyrotropin-releasing hormone pathways, increased the number of Fos-positive cells in the caudal, middle and rostral parts of the parapyramidal region to 4.3+/-0.4, 9.4+/-0.9 and 18.4+/-1.6/section, respectively, compared with 0.1+/-0. 1, 0.1+/-0.0 and 0.7+/-0.6/section, respectively, in rats maintained at room temperature. Most of the Fos-labeled cells co-expressed pro-thyrotropin-releasing hormone messenger RNA signal and/or were serotonin immunoreactive. These data show that chemical activation of neurons in the parapyramidal region results in a vagal-dependent stimulation of gastric acid secretion and that acute cold exposure activates parapyramidal neurons containing pro-thyrotropin-releasing hormone and/or serotonin, suggesting a potential role of the parapyramidal region, in addition to the caudal raphe nuclei, as medullary sites involved in the vagal regulation of gastric function.

Animals↗
PubMed2000

Characterization of a thermostable DNA glycosylase specific for U/G and T/G mismatches from the hyperthermophilic archaeon Pyrobaculum aerophilum.

U/G and T/G mismatches commonly occur due to spontaneous deamination of cytosine and 5-methylcytosine in double-stranded DNA. This mutagenic effect is particularly strong for extreme thermophiles, since the spontaneous deamination reaction is much enhanced at high temperature. Previously, a U/G and T/G mismatch-specific glycosylase (Mth-MIG) was found on a cryptic plasmid of the archaeon Methanobacterium thermoautotrophicum, a thermophile with an optimal growth temperature of 65 degrees C. We report characterization of a putative DNA glycosylase from the hyperthermophilic archaeon Pyrobaculum aerophilum, whose optimal growth temperature is 100 degrees C. The open reading frame was first identified through a genome sequencing project in our laboratory. The predicted product of 230 amino acids shares significant sequence homology to [4Fe-4S]-containing Nth/MutY DNA glycosylases. The histidine-tagged recombinant protein was expressed in Escherichia coli and purified. It is thermostable and displays DNA glycosylase activities specific to U/G and T/G mismatches with an uncoupled AP lyase activity. It also processes U/7,8-dihydro-oxoguanine and T/7,8-dihydro-oxoguanine mismatches. We designate it Pa-MIG. Using sequence comparisons among complete bacterial and archaeal genomes, we have uncovered a putative MIG protein from another hyperthermophilic archaeon, Aeropyrum pernix. The unique conserved amino acid motifs of MIG proteins are proposed to distinguish MIG proteins from the closely related Nth/MutY DNA glycosylases.

Amino Acid Sequence↗
PubMed2000

Fluid transport by cultured corneal epithelial cell layers.

BACKGROUND/AIMS: Fluid transport across the in vitro corneal epithelium is short lived, hence difficult to detect and characterise. Since stable rates of fluid transport across several cultured epithelial cell layers have been demonstrated, the behaviour of confluent SV40 transformed rabbit corneal epithelial cells (tRCEC) grown on permeable supports was examined. METHODS: Fluid transport was determined with a nanoinjector volume clamp; the specific electrical resistance of the layers was 184 (SEM 9) Omega cm(2). tRCEC layers transported fluid (from basal to apical) against a pressure head of 3 cm H(2)O for 2-3 hours. RESULTS: In the first hour, the rate of fluid transport was 5.2 (0.5) microl/h/cm(-2) (n=23), which is comparable with that found in other epithelia. Fluid transport was completely inhibited in 15-30 minutes by either 100 microM ouabain (n=6), 50 microM bumetanide (n=6), or 1 microM endothelin-1 (ET-1; n=6). Preincubation with 10 microM BQ123 (an ET(A) receptor antagonist) obviated inhibition by ET-1 (n=6). ET-1 also caused a 22% decrease in specific resistance. CONCLUSIONS: Fluid transport appears to depend on transepithelial Cl(- )transport since (1) their directions are the same (stroma-->tear), and (2) both bumetanide and ouabain inhibit it with similar time course. tRCEC appear useful to investigate aspects of the physiology and pharmacology of fluid transport across this layer, including receptor mediated control of this process.

Animals↗
PubMed2000

Familial expression of anti-Saccharomyces cerevisiae mannan antibodies in affected and unaffected relatives of patients with Crohn's disease.

BACKGROUND: Crohn's disease is a familial disorder, and antiglycan antibodies to the cell wall mannan of Saccharomyces cerevisiae (ASCA) are highly correlated with Crohn's disease. AIMS: To determine whether there is a familial pattern for expression of serum levels of anti-mannan Ig, and whether this trait is expressed in clinically unaffected Crohn's disease family members. METHODS: 349 patients with Crohn's disease, 87 Crohn's disease affected relatives, 333 inflammatory bowel disease (IBD) free relatives, 58 spouses, and 190 healthy control patients were studied. Serum IgG and IgA binding activity to S cerevisiae cell wall mannan was quantitated by ELISA. RESULTS: A high percentage of patients with Crohn's disease (51.9%) and affected family members (56.3%) were seropositive for anti-mannan Ig, compared with the normal control population (3.7%). Seropositive and seronegative phenotypes of Crohn's disease probands were correlated among all affected relatives, and this association was stronger in affected first degree relatives. Statistical intraclass correlations of quantitative anti-mannan Ig levels revealed significantly less variation within, rather than between families. A significant familial aggregation was observed for affected relatives; this was even stronger for unaffected relatives. While a significant familial aggregation was observed among unaffected siblings pairs, there was no significant correlation among marital pairs. CONCLUSION: Results show that anti-mannan Ig in family members affected and unaffected with Crohn's disease is a familial trait for both affected and unaffected relatives. The lack of concordance in marital pairs indicates that familiality is due in part to a genetic factor or childhood environmental exposure.

Adult↗
PubMed1999

Glucose control and long-term survival in biobreeding/Worcester rats after intraperitoneal implantation of hydrophilic macrobeads containing porcine islets without immunosuppression.

BACKGROUND: We investigated the effectiveness of implanted macrobeads containing porcine islets as long-term therapy for type I diabetes mellitus in Biobreeding/Worcester (BB/Wor) rats, an animal model of spontaneous type I human diabetes. End points included acute control of glucose, weight gain, survival time, and the renal changes associated with diabetes. MATERIALS AND METHODS: Eighteen chronic spontaneously diabetic BB/Wor rats were each implanted with 56-150 porcine islet macrobeads secreting 1.3-5.2 U of insulin/24 hr in culture medium at 37 degrees C. Their clinical courses and selective histological observations were compared with those of animals maintained on Linplant insulin-release implants (6 rats) or protamine zinc insulin alone (10 rats). RESULTS: The rats that underwent porcine islet macrobead implantation (PIMI) survived for a mean of 171 days (range, 79-288) after implantation without exogenous insulin, immunosuppressive treatment, or lactated Ringer's therapy. All appeared healthy and maintained their body weights (mean 356+/-21 g) throughout this period, even though their nonfasting blood glucose levels fluctuated significantly, with the mean for the group being 245+/-102 mg/dl (range, 157-320 mg/dl). There was mild glucosuria in some animals. In comparison, the 10 BB/Wor rats maintained on exogenous protamine zinc insulin had a mean survival time of 53 days (range, 10-217), a "last entry" mean body weight of 283+/-23 g, and a mean nonfasting glucose level of 340+/-90 mg/dl. The six Linplant implant animals had a mean survival time of 164 days (range, 1-264 days), a "last entry" mean body weight of 374+/-21 g, and a mean nonfasting glucose level of 189+/-91 mg/dl (range, 135-219). Episodes of ketonuria, abrupt loss of body weight, dehydration, and symptomatic hypoglycemia were more common in both these groups than in the PIMI animals. Glucose tolerance tests comparing diabetic animals treated with porcine islet macrobead implants, exogenous insulin-treated diabetic BB/Wor rats, and normal nondiabetic Wistar-Furth rats showed that the responses of those with the macrobead implants were similar to those of the normal rats, while the exogenous insulin-treated diabetic BB/Wor rats had the expected abnormal responses. Light microscopic examination of the PIMI and Linplant animals' kidney sections appeared normal, whereas those of the exogenous insulin-injected BB rats showed moderate focal tubular atrophy and an increased mesangial matrix. Macrobeads retrieved from the peritoneal cavity at necropsy were found to secrete insulin, C-peptide, and glucagon, indicating that they were still functional after 199 or more days in the peritoneal cavity. CONCLUSIONS: Our results indicate that macrobeads containing porcine islets implanted intraperitoneally in natural insulin-dependent diabetic BB/Wor rats are capable of normalizing glucose control, permitting a normal life span, and preventing the renal changes normally associated with diabetes. Therefore, further short- and long-term studies of porcine islet macrobead implantation in chemically induced and naturally occurring diabetes in rodents, as well as larger animals including dogs, monkeys and possibly humans, are merited.

Animals↗
PubMed1999

Hyperthyroidism decreases thyrotropin-releasing hormone gene expression in the caudal raphe nuclei and the parapyramidal regions in rats.

Altered thyroid statuses are associated with autonomic disorders. Medullary thyrotropin-releasing hormone (TRH) and substance P (SP) regulate autonomic nervous activity. The influences of thyroid statuses on TRH and SP gene expressions in the caudal raphe nuclei and the parapyramidal regions were studied using quantitative in situ hybridization histochemistry. In male rats thyroidectomized (Tx) for 30 days, the serum T4 levels decreased by 64% and the medullary pro-TRH mRNA signals (silver grains per neuron) significantly increased by 32-45%. These changes were prevented by daily i.p. T4 (2 microg/100 g) injection in Tx rats. In sham operated/T4 (20 microg/100 g, daily) injected rats, T4 levels significantly increased by 88% and the silver grains decreased by 38-40%. Medullary SP mRNA signals were not significantly changed by altering thyroid status. These results support the concept that thyroid hormone regulates medullary TRH gene expression by negative feedback.

Animals↗
PubMed1999

Permanent cardiovascular protection from hypertension by the AT(1) receptor antisense gene therapy in hypertensive rat offspring.

Our previous studies have demonstrated that the introduction of angiotensin II type I receptor antisense (AT(1)R-AS) cDNA by a retrovirally mediated delivery system prevents the development of hypertension in the spontaneously hypertensive rat (SHR), an animal model for primary hypertension in humans. These results have led us to propose the hypothesis that an interruption of the renin-angiotensin system (RAS) activity at a genetic level would prevent hypertension on a permanent basis. F(1) and F(2) generations of offspring from a retroviral vector, LNSV- and LNSV-AT(1)R-AS-treated SHR, were generated, and various physiological parameters indicative of hypertension were studied and compared with those of their parents to investigate this hypothesis. Both F(1) and F(2) generations of LNSV-AT(1)R-AS-treated SHR expressed a persistently lower blood pressure, decreased cardiac hypertrophy and fibrosis, decreased medial thickness, and normalization of renal artery excitation-contraction coupling, Ca(2+) current, and [Ca(2+)](i) when compared with offspring derived from the LNSV-treated SHR. In fact, the magnitude of the prevention of these pathophysiological alterations was similar to that observed in the LNSV-AT(1)R-AS-treated SHR parent. The prevention of cardiovascular pathophysiology and expression of normotensive phenotypes are, at least in part, a result of integration and subsequent transmission of AT(1)R-AS from the SHR parents to offspring. These data demonstrate that a single intracardiac injection of LNSV-AT(1)R-AS causes a permanent cardiovascular protection against hypertension as a result of a genomic integration and germ line transmission of the AT(1)R-AS in the SHR offspring.

Animals↗
PubMed1999

Oryza sativa PSK gene encodes a precursor of phytosulfokine-alpha, a sulfated peptide growth factor found in plants.

Phytosulfokine-alpha [PSK-alpha, Tyr(SO(3)H)-Ile-Tyr(SO(3)H)-Thr-Gln], a sulfated mitogenic peptide found in plants, strongly promotes proliferation of plant cells in culture at very low concentrations. Oryza sativa PSK (OsPSK) cDNA encoding a PSK-alpha precursor has been isolated. The cDNA is 725 base pairs long, and the 89-aa product, preprophytosulfokine, has a 22-aa hydrophobic region that resembles a cleavable leader peptide at its NH(2) terminus. The PSK-alpha sequence occurs only once within the precursor, close to the COOH terminus. [Ser(4)]PSK-alpha was secreted by transgenic rice Oc cells harboring a mutated OsPSK cDNA, suggesting proteolytic processing from the larger precursor, a feature commonly found in animal systems. Whereas PSK-alpha in conditioned medium with sense transgenic Oc cells was 1.6 times as concentrated as in the control case, antisense transgenic Oc cells produced less than 60% of the control level. Preprophytosulfokine mRNA was detected at an elevated constitutive level in rice Oc culture cells on RNA blot analysis. Although PSK-alpha molecules have never been identified in any intact plant, reverse transcription-PCR analysis demonstrated that OsPSK is expressed in rice seedlings, indicating that PSK-alpha may be important for plant cell proliferation both in vitro and in vivo. DNA blot analysis demonstrated that OsPSK homologs may occur in dicot as well as monocot plants.

Amino Acid Sequence↗
PubMed1999

Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association.

The PTEN tumor suppressor is mutated in diverse human cancers and in hereditary cancer predisposition syndromes. PTEN is a phosphatase that can act on both polypeptide and phosphoinositide substrates in vitro. The PTEN structure reveals a phosphatase domain that is similar to protein phosphatases but has an enlarged active site important for the accommodation of the phosphoinositide substrate. The structure also reveals that PTEN has a C2 domain. The PTEN C2 domain binds phospholipid membranes in vitro, and mutation of basic residues that could mediate this reduces PTEN's membrane affinity and its ability to suppress the growth of glioblastoma tumor cells. The phosphatase and C2 domains associate across an extensive interface, suggesting that the C2 domain may serve to productively position the catalytic domain on the membrane.

Amino Acid Sequence↗
PubMed1999

Production of human alloreactive antibodies by uremic sensitized lymphocytes engrafted in severe combined immunodeficient mice.

BACKGROUND: Numerous studies have documented antibody responses to nominal antigens in human peripheral blood lymphocyte (hu-PBL)-severe combined immunodeficient (SCID) mice engrafted with PBL. We suggest, therefore, that engraftment of SCID mice by allosensitized cells produces alloreactive antibodies (allo-Ab). As such, SCID mice can be used as a model to examine the cellular basis of the sustenance of humoral alloresponses. METHODS: C.B-17 SCID mice were engrafted intraperitoneally with PBL from sensitized uremic patients for 5 weeks and classified into the following: group 1, 8 mice engrafted with unactivated cells (n = 5; n = sensitized patients); group 2, 6 mice engrafted with unactivated PBL (n = 3) followed 2 days later by in vivo activation with interleukin-2 (IL-2) and lipopolysaccharide (LPS); group 3, 11 mice engrafted with cells preactivated in vitro with IL-2 and LPS (n = 6); group 4, 9 mice engrafted with cells preactivated with irradiated allogeneic transformed B cells, IL-2, and LPS (n = 5); group 5, 10 mice engrafted with cells preactivated with IL-2, LPS, and HLA class II allopeptides and adjuvant (n = 6); group 6, 8 control mice engrafted with control cells preactivated with IL-2 and LPS. Two weeks later, each group was rechallenged by the same stimuli. Allo-Ab production was measured by the panel-reactive antibody PRA-STAT ELISA method. Results. Allo-Ab was produced in 54.5% of group 3, 43% of group 4; 80% of group 5, and 0% of groups 1, 2, and 6. The ratio of alloreactive positive wells in the allo-Ab-producing PBL-hu-SCID mice to that present in the respective patient's sera was 82%, 52%, and 87% in groups 3, 4, and 5, respectively. Conclusions. The study demonstrates the feasibility of using the hu-PBL-SCID model to study alloreactive memory B-cell function in humans. Discrete HLA-class allopeptides (group 5) appeared more potent allo-Ab producers than allogeneic cells (group 4).

Adjuvants, Immunologic↗
PubMed1999

An integrated decoupler for capillary electrophoresis with electrochemical detection: application to analysis of brain microdialysate.

An approach to capillary electrophoresis with electrochemical detection (CE-EC) suitable for determination of dopamine in 1-min brain microdialysate samples is described. The CE-EC system includes an electrochemical detection cell that permits easy, precise, and permanent alignment of a carbon fiber microelectrode with a separation capillary (30-micron i.d., 75-cm length). Amperometric detection was performed at a constant applied potential of 600 mV with respect to a Ag/AgCl reference electrode. Decoupling of the electrophoretic current from the amperometric detector was accomplished with an integrated end-column decoupler prepared by etching the capillary outlet with HF. The decoupler produces baseline noise of 50 fA, or less, in the presence of 10-20-muA current in the separation capillary. The low baseline noise affords low mass (attomoles) and low concentration (nanomolar) detection limits for dopamine and 4-methylcatechol. A peak attributable to dopamine was identified in electropherograms of brain microdialysate samples obtained from anesthetized rats. Identification of the dopamine peak was confirmed by pharmacological methods. Dopamine was readily detected in 1-min brain microdialysate samples. The dopamine concentration in 1-min brain microdialysis samples was significantly altered by drug treatments and by brief electrical stimulation of dopaminergic axons.

Animals↗
PubMed1999

Isolation of high-affinity peptide antagonists of 14-3-3 proteins by phage display.

The 14-3-3 proteins interact with diverse cellular molecules involved in various signal transduction pathways controlling cell proliferation, transformation, and apoptosis. To aid our investigation of the biological function of 14-3-3 proteins, we have set out to identify high-affinity antagonists. By screening phage display libraries, we have identified a set of peptides which bind 14-3-3 proteins. One of these peptides, termed R18, exhibited a high affinity for different isoforms of 14-3-3 with estimated K(D) values of 7-9 x 10(-)(8) M. Recognition of multiple isoforms of 14-3-3 suggests the targeting of R18 to a structure that is common among 14-3-3 proteins, such as the conserved ligand-binding groove. Indeed, mutations that alter critical residues in the ligand-binding site of 14-3-3 drastically decreased the level of 14-3-3-R18 association. R18 efficiently blocked the binding of 14-3-3 to the kinase Raf-1, a physiological ligand of 14-3-3, and effectively abolished the protective role of 14-3-3 against phosphatase-induced inactivation of Raf-1. The cocrystal structure of R18 in complex with 14-3-3zeta revealed the occupancy of the general binding groove of 14-3-3zeta by R18, explaining the potent inhibitory effect of R18 on 14-3-3-ligand interactions. Such a well-defined peptide will be an effective tool for probing the role of 14-3-3 in various signaling pathways, and may lead to the development of 14-3-3 antagonists with pharmacological applications.

14-3-3 Proteins↗
PubMed1999

Effect of thioacetamide on the hepatic expression of gamma-glutamylcysteine synthetase subunits in the Rat.

Glutathione (GSH) is the main nonprotein thiol important in antioxidant defense and maintenance of the intracellular redox state. A major determinant of the rate of GSH synthesis is the activity of the rate-limiting enzyme, gamma-glutamylcysteine synthetase (GCS). A heavy (HS) and light subunit (LS) make up GCS; oxidative stress regulates both transcriptionally. cis-Acting elements important for the oxidative stress-induced transcriptional up-regulation of both subunits are antioxidant response element (ARE) and activator protein-1 (AP-1) site. The nuclear factor-kappaB (NF-kappaB) binding site may also regulate the heavy subunit. Increased GSH and gamma-glutamyltranspeptidase are often observed in preneoplastic hepatocyte nodules and may be important in hepatocarcinogenesis. The current work examined the effect of a commonly used hepatocarcinogen, thioacetamide (TAA), on the expression of GCS subunits. After 3 weeks of TAA treatment, liver GSH level remained unchanged despite significant oxidative stress as measured by the thiobarbituric acid reactive substance assay. The mRNA levels of GCS-HS and GCS-LS increased six- and fourfold, respectively, and the protein level of GCS-HS and GCS activity all increased. Electrophorectic mobility shift assay showed binding to ARE, AP-1, and NF-kappaB probes all increased. These results suggest TAA treatment increased hepatic GCS subunit expression and GCS activity by inducing oxidative stress and increasing the binding to redox-sensitive cis-acting elements important for transcriptional up-regulation of GCS. This is the first in vivo study that examined the effect of a hepatocarcinogen on GCS expression.

Animals↗
PubMed1999

Rapid, direct determination of polyphenols in tea by reversed-phase column liquid chromatography.

Column liquid chromatography on a C18-bonded silica column with water-methanol-acetic acid as eluent was used to determine polyphenols and caffeine in tea. Without any pretreatment, catechin, epicatechin gallate, epigallocatechin gallate, epigallocatechin, epicatechin and caffeine were separated successfully within 15 min. The detection limits (S/N = 3) of polyphenols studied were 1.8-24 mg/l at a detection wavelength 270 nm. The linear range of the peak area calibration curves for the analytes were over two orders of magnitude with a correlation coefficient of 0.996-0.999. Using this method, some Chinese tea samples were analyzed with a good reproducibility (RSD are below 5%).

Caffeine↗
PubMed1999

Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome.

Glypicans are a family of heparan sulfate proteoglycans that are linked to the cell surface through a glycosyl-phosphatidylinositol anchor. One member of this family, glypican-3 (Gpc3), is mutated in patients with the Simpson-Golabi-Behmel syndrome (SGBS). These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms. The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II. However, there is still no biochemical evidence indicating that GPC3 plays such a role.Here, we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also display mandibular hypoplasia and an imperforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element. The degree of developmental overgrowth of the GPC3-deficient mice is similar to that of mice deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator of IGF-II. Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates.

Abnormalities, Multiple↗