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Y Wu

Publications and source records attributed to Y Wu.

At least 757 records · Page 42Linked to original sources
PubMed1997

Characterization of beta-glucuronidase in the retinal pigment epithelium.

PURPOSE: To study the biochemical and molecular characteristics of the lysosomal enzyme beta-glucuronidase (GUSB) in the retinal pigment epithelium (RPE) and other tissues of different species. METHODS: Freshly isolated and cultured cells were harvested, and GUSB activity was measured fluorimetrically in cell homogenates or tissue culture media using the synthetic substrate 4-methyl-umbelliferyl beta-D-glucuronide (4-MUG). The temperature and pH optima, and thermal stability of GUSB in the RPE and fibroblasts were established. Distribution of glycosaminoglycans (GAGs), the natural substrates of GUSB, in the RPE and fibroblast cell layer and media was examined by cellulose acetate electrophoresis following 72 h of metabolic labeling with Na2(35)SO4. Total or poly A(+)-RNA isolated from cells or tissues of different species were examined in Northern blots to identify GUSB mRNA transcripts. RESULTS: Among all the species, the activity of GUSB and its mRNA level was found to be consistently high in RPE cells. In RPE cultures, the activity was detected in the cell layer and the media, and the activity decreased in both compartments with serial passage. While the temperature and pH optima for the enzyme activity was similar across the species, the thermal stability was remarkably different. The GAG profiles in RPE cells were different from fibroblasts. Supplementation of the cultured cells with selected GAGs moderately increased the GUSB activity. A GUSB transcript was detected in all the tissues examined. In man, mouse, dog, and cat the size of the transcript was 2.4 kb, while the rat GUSB transcript was 2.7 kb. CONCLUSIONS: The ubiquitous distribution of GUSB was evident from the biochemical and molecular studies. Presence of a high level of GUSB activity in the RPE makes it an ideal model for studies of this enzyme both in normal as well as in diseases resulting in GUSB deficiency.

Animals↗
PubMed1997

Microsatellite instability and loss of heterozygosity in chromosomes 9 and 16 in human breast epithelial cells transformed by chemical carcinogens.

Microsatellite instability (MSI) and loss of heterozygosity (LOH) in chromosomes 9 and 16 have been reported in human breast cancers. In order to determine whether changes in these chromosomes play a role in the initiation and progression of this disease, we performed microsatellite polymorphism analyses in human breast epithelial cells (HBEC) transformed by chemical carcinogens, an in vitro system that recapitulates various stages of neoplastic transformation. In this experimental system we studied the mortal HBEC MCF-10M, immortal MCF-10F cells, derived from MCF-10M cells, and clones derived from MCF-10F cells treated with benzo[a]pyrene (B[a]P) (BP1 and BP1E) and 7,12-dimethylbenz[a]anthracene (DMBA) (D3 and D3-1). The four clones of transformed cells were injected into severe combined immunodeficient (SCID) mice. Only BP1-E cells induced the formation of tumors, designated BP1E-Tp cells. These cells originated six additional tumors, designated BP1E-Tf no. 1 through Tf no. 6. Microsatellite analyses were carried out using five markers for chromosome 9 and 20 for chromosome 16. There was no evidence of MSI or LOH in clones BP1 and BP1E when compared with the MCF-10M and MCF-10F cells, whereas BP1E-Tp cells and Bp1E-Tf no. 1-Tf no. 6 tumors exhibited MSI at loci p23 and p21, and LOH at p21-22 of chromosome 9. They also exhibited MSI and LOH at multiple loci of both the short and long arms of chromosome 16, i.e. p13.13, p13.3, p12, q12.1, q12.2, q23 and q24, to which putative tumor suppressor genes have been localized. Clones D3 and D3-1 exhibited no genomic changes in chromosome 9, but did show MSI at locus q12.1 of chromosome 16 using marker D16S285. Although the cells treated with DMBA expressed early phenotypes of neoplastic transformation, they were not tumorigenic, and also manifested fewer changes than the tumorigenic BP1E-Tp cells and the tumors BP1E-Tf. The changes in chromosomes 9 and 16 observed in these latter ones indicated an association with the expression of tumorigenesis, which represents a late event in the progression of the neoplastic transformation of HBEC. Of interest was the observation that HBEC transformed by chemical carcinogens in vitro express genomic changes similar to those found in spontaneous breast carcinomas.

Animals↗
PubMed1997

Molecular cloning, expression and subcellular localization of a BiP homolog from rice endosperm tissue.

The ER luminal binding protein, BiP, has been linked to prolamine protein body formation in rice. To obtain further information on the possible role of this chaperone in protein body formation we have cloned and sequenced a BiP cDNA homolog from rice endosperm. The rice sequence is very similar to the maize BiP exhibiting 92% nucleotide identity and 96% deduced amino acid sequence identity in the coding region. Substantial amino acid sequence homology exists between rice BiP and BiP homologs from several other plant and animal species including long stretches of conservation through the amino-terminal ATPase domain. Considerable variation, however, is observed within the putative carboxy-terminal peptide-binding domain between the plant and nonplant BiP sequences. A single hand of approximately 2.4 kb was visible when RNA gel blots of total RNA purified from seed tissue were probed with radiolabeled rice BiP cDNA. This band increased in intensity during seed development up to 10 days after flowering, and then decreased gradually until seed maturity. Protein gel blots indicated that BiP polypeptide accumulation parallels that of the prolamine polypeptides throughout seed development. Immunocytochemical analysis demonstrated that BiP is localized in a non-stochastic fashion in the endoplasmic reticulum membrane complex of developing endosperm cells. It is abundant on the periphery of the protein inclusion body but not in the central portion of the protein body or in the cisternal ER membranes connecting the protein bodies. These data support a model which proposes that BiP associates with the newly synthesized prolamine polypeptide to facilitate its folding and assembly into a protein inclusion body, and is then recycled.

Amino Acid Sequence↗
PubMed1997

Expression of the opioid growth factor, [Met5]-enkephalin, and the zeta opioid receptor in head and neck squamous cell carcinoma.

Despite the prevalence of cancers of the head and neck, survival rates have not changed in the past few decades. Recent work has implicated peptide growth factors and their receptors in the genesis and progression of head and neck squamous cell carcinoma. Opioid growth factor (OGF, [Met5]-enkephalin) is a tonically active, autocrine and/or paracrine produced, inhibitory factor that influences the growth of normal and abnormal cells and tissues. This peptide interacts with the zeta (zeta) opioid receptor to modulate cellular proliferation, migration, and survival. Both OGF and the zeta receptor are present in mammalian tongue epithelium and skin, and modulate DNA synthesis. In the present study we examined the presence and distribution of OGF and the zeta opioid receptor in the head and neck squamous cell carcinomas from seven individuals. All specimens expressed this growth factor and its receptor regardless of tumor stage, location, and histologic grade. Immunoreactivity for both OGF and the zeta receptor were associated with the cytoplasm but not the nucleus in cells of each of these carcinomas. Our findings that a potent negative growth regulator and its receptor are present in head and neck squamous cell carcinoma lead us to suggest that OGF may modulate the growth of these types of cancers.

Aged↗
PubMed1997

Sequential subtraction scintigraphy with 99Tcm-RBC for the early detection of gastrointestinal bleeding and the calculation of bleeding rates: phantom and animal studies.

To improve the detectability of gastrointestinal (GI) bleeding, we have developed a new method, 'sequential subtraction scintigraphy' (SSS) with 99Tcm-labelled red blood cells (RBC). Sequential subtraction scintigrams were obtained by subtracting 5 min interval images from each other using a digital gamma camera. With this method, we are able to detect the bleeding site and calculate the bleeding rate earlier because of the lower background activity. The results of the present study demonstrate that the minimum detectable bleeding rate was 0.05 ml min-1 in both a phantom and an animal model. The minimum detectable activity volumes within 10 min were 0.5 ml by SSS and more that 3 ml by conventional non-subtraction scintigraphy (CNS). The bleeding rates calculated with the subtraction method correlated well with the actual syringe pump rates. The detectability of GI bleeding by SSS and CNS in animal models was compared using the area under receiver operator characteristic (ROC) curves. The results showed that SSS significantly increased the area under the ROC curves from 0.55 +/- 0.05 to 0.79 +/- 0.04 for the 10 min image set and from 0.65 +/- 0.05 to 0.83 +/- 0.04 for the 30 min image set (Z = 5.45, P < 0.0001 and Z = 4.36, P < 0.0001, respectively). These results suggest that sequential subtraction scintigraphy with 99Tcm-RBC is an effective method for the early detection of GI bleeding when compared with the conventional non-subtraction method.

Adult↗
PubMed1997

Involvement of Fnr and ArcA in anaerobic expression of the tdc operon of Escherichia coli.

Anaerobic expression of the tdcABC operon in Escherichia coli, as measured by LacZ activity from single-copy tdc-lacZ transcriptional and translational fusions, is greatly reduced in strains lacking two global transcriptional regulators, Fnr and ArcA. The nucleotide sequence of the tdc promoter around -145 shows significant similarity with the consensus Fnr-binding site; however, extensive base substitutions within this region had no effect on Fnr regulation of the tdc genes. A genetic analysis revealed that the effect of Fnr on tdc is not mediated via ArcA. Furthermore, addition of cyclic AMP to the anaerobic incubation medium completely restored tdc expression in fnr and arcA mutants as well as in strains harboring mutations in the Fnr- and ArcA-dependent pfl gene and the Fnr-regulated glpA and frd genes. These results, taken together with the earlier finding that tdc expression is subject to catabolite repression by intermediary metabolites, strongly suggest that the negative regulatory effects of mutations in the fnr and arcA genes are mediated physiologically due to accumulation of a metabolite(s) which prevents tdc transcription in vivo.

Amino Acid Transport Systems, Neutral↗
PubMed1997

Left ventricular pressure response to small-amplitude, sinusoidal volume changes in isolated rabbit heart.

The objective was to determine the dynamics of contractile processes from pressure responses to small-amplitude, sinusoidal volume changes in the left ventricle of the beating heart. Hearts were isolated from 14 anesthetized rabbits and paced at 1 beats/s. Volume was perturbed sinusoidally at four frequencies (f) (25, 50, 76.9, and 100 Hz) and five amplitudes (0.50, 0.75, 1.00, 1.25, and 1.50% of baseline volume). A prominent component of the pressure response occurred at the f of perturbation [infrequency response, delta Pf(t)]. A model, based on cross-bridge mechanisms and containing both pre- and postpower stroke states, was constructed to interpret delta Pf(t). Model predictions were that delta Pf(t) consisted of two parts: a part with an amplitude rising and falling in proportion to the pressure around that which delta Pf(t) occurred [Pr(t)], and a part with an amplitude rising and falling in proportion to the derivative of Pr(t) with time. Statistical analysis revealed that both parts were significant. Additional model predictions concerning response amplitude and phase were also confirmed statistically. The model was further validated by fitting simultaneously to all delta Pf(t) over the full range of f and delta V in a given heart. Residual errors from fitting were small (R2 = 0.978) and were not systematically distributed. Elaborations of the model to include noncontractile series elastance and distortion-dependent cross-bridge detachment did not improve the ability to represent the data. We concluded that the model could be used to identify cross-bridge rate constants in the whole heart from responses to 25- to 100-Hz sinusoidal volume perturbations.

Animals↗
PubMed1997

Calcium transient alternans in blood-perfused ischemic hearts: observations with fluorescent indicator fura red.

Ischemia produces striking electrophysiological abnormalities in blood-perfused hearts that may be caused, in part, by effects of ischemia on intracellular calcium. To test this hypothesis, intracellular Ca2+ concentration ([Ca2+]i) transients were recorded from the epicardial surface of blood- and saline-perfused rabbit hearts using the long-wavelength indicator Fura Red. Calcium transients were much larger than the movement artifact, representing up to 29% of the total signal. Switching the perfusate from saline to blood did not affect the time course of the transients or the apparent level of [Ca2+]i. Compartmentation of Fura Red fluorescence was estimated by exposure to Mn2+. The results were cytosol 60 +/- 3%, organelles 12 +/- 2%, and autofluorescence plus partly deesterified Fura Red 29 +/- 4%. [Ca2+]i transients were calibrated in situ by perfusion of the extracellular space with high-Ca2+ and Ca(2+)-free EGTA solutions. Peak systolic [Ca2+]i was 663 +/- 74 nM, and end-diastolic [Ca2+]i was 279 +/- 59 nm. Ischemia was produced by interruption of aortic perfusion for 2.5 min during pacing (150 beats/min). Ischemia produced broadening of the [Ca2+]i transient, along with beat-to-beat alternations in the peak systolic and end-diastolic level of [Ca2+]i (calcium transient alternans). [Ca2+]i transient alternans occurred in 82% of blood-perfused hearts vs. 43% of saline-perfused hearts. The discrepancy between large and small transients (mean alternans ratio) was larger in the blood-perfused hearts (0.23 +/- 0.04 vs. 0.07 +/- 0.03, P = 0.005). These observations are important because of the apparent relationship of [Ca2+]i transient alternans to electrical alternans and arrhythmias during ischemia.

Animals↗
PubMed1997

Relaxation effect of CGP-48506, EMD-57033, and dobutamine in ejecting and isovolumically beating rabbit hearts.

Because it is not known whether ejection influences the negative effect of the Ca(2+)-sensitizing drugs on ventricular relaxation, we extended our previous analysis of stress-dependent relaxation in isovolumic beats to encompass ejecting beats and evaluated the relationships between both the time of onset of relaxation and the rate of relaxation and wall stress in a broader analysis framework. Furthermore, because the sites of action of the Ca(2+)-sensitizing drugs CGP-48506 and EMD-57033 may be different, and thus CGP-48506 may have fewer adverse effects on resting muscle length or force, we compared these two drugs to test the hypothesis that CGP-48506 would have less effect than EMD-57033 on relaxation in the isolated buffer-perfused rabbit heart. This analysis of stress-dependent relaxation in both ejecting and isovolumic beats readily differentiates between the negative lusitropic effect of 2 x 10(-6) M EMD-57033, the negligible lusitropic effect of 6 x 10(-6) M CGP-48506, and the positive lusitropic effect of 1.25 x 10(-6) M dobutamine. Furthermore, comparison of the effect of the two Ca(2+)-sensitizing drugs in ejecting versus isovolumic contractions shows that CGP-48506 affects relaxation differently in ejecting contractions than it does in isovolumic contractions, whereas EMD-57033 affects relaxation similarly in both ejecting and isovolumic contractions.

Animals↗
PubMed1997

Cytokine- and virus-stimulated airway smooth muscle cells produce IL-11 and other IL-6-type cytokines.

Inflammation and smooth muscle abnormalities coexist in human airway disorders, and inflammation modulates the proliferative and contractile properties of airway smooth muscle cells. To determine whether human airway smooth muscle (HASM) cells have the ability to regulate local inflammatory processes, we characterized the interleukin (IL)-6-type cytokine production of HASM cells in vitro. We demonstrated that HASM cells are potent producers of IL-11 when stimulated with IL-1 or transforming growth factor-beta 1 (TGF-beta 1) and that IL-11 levels are synergistically increased by IL-1 and TGF-beta 1 in combination. These studies also demonstrated that IL-1 and TGF-beta 1-stimulated HASM cells produce IL-6 and leukemia inhibitory factor but not oncostatin M and that respiratory syncytial virus and parainfluenza virus type 3 stimulate HASM cell IL-11 production. Finally, they demonstrate that, in all cases, the stimulation of HASM cell IL-11 elaboration is pretranslationally mediated since cytokine- and virus-induced alterations in IL-11 protein production were associated with proportionate changes in IL-11 mRNA accumulation. HASM cells are potent producers of IL-11 and other IL-6-type cytokines and may be important regulators of local airway inflammation.

Animals↗
PubMed1997

Rhinovirus stimulation of interleukin-8 in vivo and in vitro: role of NF-kappaB.

Neutrophil infiltration is a well-documented early event in the pathogenesis of rhinovirus (RV) infections. To further understand the mechanisms responsible for this neutrophilia, we determined whether interleukin (IL)-8 was present at sites of experimental RV infection in vivo and characterized the mechanism(s) by which RV stimulates IL-8 production in vitro. IL-8 was readily detectable in the nasal washings of all normal volunteers and did not increase with sham nasal inoculation. In contrast, RV infection caused a significant additional increase in nasal IL-8, the levels of which peaked 48-72 h after virus inoculation. RV was a potent stimulator of IL-8 protein production by A549 epithelial-like cells, MRC-5 fibroblasts, and normal human bronchial epithelial cells in vitro. This induction was associated with a significant increase in IL-8 mRNA accumulation and gene transcription. RV also stimulated IL-8 promoter-driven luciferase activity. This stimulation was significantly decreased by mutation of the nuclear factor (NF)-IL-6 site and was completely abrogated by mutation of the NF-kappaB site in this promoter. In addition, NF-kappaB-DNA binding activity was rapidly induced in RV-infected cells. This inducible binding was made up of p65 and, to a lesser extent, p50 NF-kappaB moieties. These studies demonstrate that IL-8 is present in normal nasal secretions and that the levels of IL-8 are further increased after RV infection. They also demonstrate that RVs are potent stimulators of IL-8 production and that this induction is mediated, at least in part, by an NF-kappaB-dependent transcriptional activation pathway. IL-8 may contribute to the pathogenesis of RV infection, and NF-kappaB activation may be a central event in RV-induced pathologies.

Adult↗
PubMed1997

Opioid growth factor is present in human and mouse gastrointestinal tract and inhibits DNA synthesis.

Native opioid peptides serve as growth factors in a number of normal and neoplastic cells and tissues. This study investigated the influence of opioids on circadian rhythm-dependent DNA synthesis in mouse esophagus during homeostatic renewal. In contrast to a labeling index (LI) of 24.0% at 0630 and 5.5% at 1600, disruption of opioid-receptor interaction by the potent opioid antagonist naltrexone hydrochloride (NTX; 10 mg/kg) in mice resulted in an elevation of 49% in DNA synthesis of esophageal epithelial cells at 1600, but had no effect at 0630. Mice subjected to [Met5]enkephalin (1 mg/kg) had an LI that was decreased 23% from control levels at 0630, but was unaffected at 1600. This decrease in DNA synthesis was blocked by concomitant administration of naloxone (10 mg/kg); naloxone alone had no influence on cell replicative processes. In tissue culture studies, NTX and OGF markedly increased and decreased, respectively, the LI from control values. Both opioid growth factor (OGF) and its receptor, zeta, were detected in all but the cornified layer of mouse esophageal epithelium and in the epithelial cells of the stomach and small and large intestines. In addition, both peptide and receptor were observed in the basal and suprabasal cells of human esophageal epithelium. These results indicate that an endogenous opioid peptide (OGF) and its receptor (zeta) reside in gastrointestinal epithelium and play a role in cellular renewal processes in a tonically inhibitory, direct, and circadian rhythm-dependent fashion.

Animals↗
PubMed1997

Identification and characterization of the zeta-opioid receptor in developing rat heart.

Opioid growth factor (OGF; [Met5]enkephalin) inhibits DNA synthesis of epicardial and myocardial cells in the neonatal rat heart in a receptor-mediated fashion. Ligand binding assays using newborn rat heart and [3H][Met5]enkephalin were performed to characterize the receptor responsible for the cell replicative effects of OGF in developing heart. Specific and saturable binding was detected, and Scatchard analysis revealed that the data were consistent for a single binding site with a binding affinity of 6.8 +/- 0.3 nM and a binding capacity of 21.8 +/- 1.9 fmol/mg protein. Subcellular fractionation studies revealed that binding was restricted to the nuclear fraction. Competition experiments showed that cold [Met5]enkephalin was the most effective ligand at displacing [3H][Met5]enkephalin. Binding was recorded on gestation days 18 and 20, reached its highest level at birth, and steadily decreased from postnatal days 1 to 15; binding at days 21 and 35 and in adults was negligible. The function, pharmacological and biochemical characteristics, distribution, and subcellular location of this OGF receptor in developing mammalian heart are consistent with the zeta-opioid receptor.

Animals↗
PubMed1997

Induction of vascular endothelial growth factor in balloon-injured baboon arteries. A novel role for reactive oxygen species in atherosclerosis.

Neovascularization is a hallmark of neointimal formation in atherosclerotic plaques and restenotic lesions. Vascular endothelial growth factor (VEGF) promotes neovascular growth, whereas oxidative stress is a potent factor in vascular cell proliferation. To investigate the mechanisms of neovascular formation, we treated human and rat vascular smooth muscle cells (VSMCs) with H2O2. Northern blot analysis demonstrated a dose- and time-dependent increase in VEGF mRNA, with a maximum of 4-fold at 3 hours (200 mumol/L). As determined by immunoblotting and enzyme-linked immunosorbent assay, VEGF protein expression and secretion were similarly increased. Human umbilical vein endothelial cells were treated with conditioned medium from VSMCs incubated with 200 mumol/L H2O2. DNA synthesis, measured by thymidine incorporation, was increased 4-fold compared with control, an effect that was blocked by a neutralizing anti-VEGF antibody. The lipid peroxidation product 4-hydroxynonenal (1 mumol/L), an endogenous reactive oxygen species present in human atherosclerotic lesions, also increased VEGF secretion in VSMCs in a similar time-dependent fashion. Immunohistochemical staining and in situ hybridization of aortic sections from balloon-injured baboons demonstrated increased VEGF expression in discrete areas of the neointima and media compared with control sections, and expression correlated with the generation of 4-hydroxynonenal. Regulators of VEGF expression, such as reactive oxygen species, may enhance neovascularization of atherosclerotic and restenotic arteries.

Animals↗
PubMed1997

Cell death suggestive of apoptosis after spinal cord ischemia in rabbits.

BACKGROUND AND PURPOSE: After spinal cord ischemia, some neurons remain viable after an ischemic insult but may be at risk of dying during reperfusion. We searched for morphological and biochemical features of apoptosis, which is a mechanism of delayed neuronal death, in a rabbit model of spinal cord ischemia. METHODS: The infrarenal aorta of White New Zealand rabbits (n = 24) was occluded for 40 minutes using a loop tourniquet. Rabbits were killed after 12, 24, or 48 hours (n = 8 per group). The loop was placed but never tightened in sham-operated rabbits (n = 6). The lumbar segment of the spinal cord (L5 to L7) was used for morphological studies, including hematoxylin and eosin staining and a modified terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining method. Electron microscopy was used to examine ultrastructural morphology. In addition, lumbar tissue was used for biochemical investigation of DNA laddering by agarose gel electrophoresis. RESULTS: After ischemia, the affected areas contained neurons with positive TUNEL staining. Positive neurons were located in laminae III to IX, although most were concentrated in the intermediate and ventral areas. Adjacent sections stained with hematoxylin and eosin exhibited ischemic cell changes (red and ghost neurons), while apoptotic bodies were also apparent. In addition, electron microscopy of ischemic tissue samples exhibited ultrastructural characteristics of apoptosis, including nuclear condensation and relatively normal organelle morphology. Finally, isolated DNA revealed a ladder on agarose gel electrophoresis, indicating DNA fragmentation into approximately 180 multiples of base pairs. CONCLUSIONS: Spinal cord ischemia in rabbits induces morphological and biochemical changes suggestive of apoptosis. These data raise the possibility that apoptosis contributes to neuronal cell death after spinal cord ischemia.

Animals↗
PubMed1997

A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma.

Specific mutations in the ret protooncogene have been found associated with multiple endocrine neoplasia type 2A (MEN 2A) and type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). Mutations in one of five cysteine residues in the extracellular domain have been found in over 95% of families with MEN 2A and 88% of families with FMTC. In MEN 2B patients, a specific mutation at codon 918, substituting a threonine for a methionine, has been found in 95% of cases. In FMTC, in addition to the mutations of the extracellular cysteines, three intracellular base pair changes have been reported at codons 768 and 804. Here we describe a novel intracellular mutation in exon 15 of the ret gene that leads to the substitution of an alanine for a serine at codon 891 in a family with medullary thyroid carcinoma. This amino acid change may be important in determining substrate specificity or, alternatively, may play a role in ATP binding.

Amino Acid Sequence↗
PubMed1997

Novel mutations and a mutational hotspot in the MODY3 gene.

Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha) located on chromosome 12q. We have identified four novel HNF-1alpha missense mutations in MODY3 families. In four additional and unrelated families, we observed an identical insertion mutation that had occurred in a polycytidine tract in exon 4. Among those families, one exhibited a de novo mutation at this location. We propose that instability of this sequence represents a general mutational mechanism in MODY3. We observed no HNF-1alpha mutations among 86 unrelated late-onset diabetic patients with relative insulin deficiency. Hence mutations in this gene appear to be most strongly associated with early-onset diabetes.

Chromosomes, Human, Pair 12↗