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1.
Hum Mutat ; 26(4): 308-14, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16116615

ABSTRACT

Mucolipidosis types II and III are autosomal recessive inherited diseases caused by a deficiency in the lysosomal enzyme N-acetylglucosamine-1 phosphotransferase (GlcNAc-phosphotransferase), which adds phosphate to function as a recognition marker for the uptake and transport of lysosomal enzymes. We investigated mutations in the GNPTA (MGC4170) gene, which codes for the alpha/beta subunits of phosphotransferase, and in the GNPTAG gene, which codes for its gamma subunits in five Korean patients with mucolipidosis type II or IIIA. We identified seven mutations in the GNPTA gene, but none in GNPTAG. The mutations in type II patients included p.Q104X (c.310C>T), p.R1189X (c.3565C>T), p.S1058X (c.3173C>G), p.W894X (c.2681G>A), and p.H1158fsX15 (c.3474_3475delTA), all of which are nonsense or frameshift mutations. However, a splicing site mutation, IVS13+1G>A (c.2715+1G>A) was detected along with a nonsense or a frameshift mutation (p.R1189X or p.E858fsX3 (c.2574_2575delGA)) in two mucolipidosis type IIIA patients. This report shows that mutations in the GNPTA gene coding for the alpha/beta subunits of phosphotransferase, and not mutations in the GNPTAG gene, account for most of the genetic mutations found in Korean patients with mucolipidosis type II or IIIA.


Subject(s)
Asian People/genetics , Mucolipidoses/genetics , Mutation , Transferases (Other Substituted Phosphate Groups)/genetics , Adolescent , Adult , Child , Child, Preschool , DNA Mutational Analysis , Female , Genetic Testing , Humans , Infant , Infant, Newborn , Male , Mucolipidoses/metabolism , Transferases (Other Substituted Phosphate Groups)/metabolism
2.
Nephron Exp Nephrol ; 100(2): e85-94, 2005.
Article in English | MEDLINE | ID: mdl-15775722

ABSTRACT

BACKGROUND/AIM: Induction of heat shock protein 70 (HSP70) is important in the tolerance of subsequent ischemia-reperfusion (I/R) injury. The aim of this study was to evaluate the effect of HSP70 induction by 1,25-dihydroxyvitamin D3 (VD3) on subsequent I/R injury in rats. METHODS: HSP70 was induced in Sprague-Dawley rats by VD3 treatment for 7 days, and the effect of VD3 pretreatment on subsequent I/R injury was evaluated in terms of renal function, tubular necrosis score, tumor necrosis factor alpha mRNA expression, mitogen-activated protein kinase expression, and proliferating cell nuclear antigen expression. RESULTS: VD3 treatment increased HSP70 expression which was localized to renal tubular cells in the outer medulla. Pretreatment with VD3 before I/R injury resulted in (1) decreased blood urea nitrogen and serum creatinine levels; (2) decreased tubular cell necrosis; (3) increased tubular cell proliferation as determined by proliferating cell nuclear antigen expression; (4) decreased tumor necrosis factor alpha mRNA expression, and (5) increased extracellular signal regulated protein kinase and decreased c-Jun N-terminal kinase expression. CONCLUSION: Our study demonstrates that VD3 is a nontoxic inducer of HSP70 and exerts a protective effect against subsequent I/R injury.


Subject(s)
Calcitriol/pharmacology , Calcium Channel Agonists/pharmacology , HSP70 Heat-Shock Proteins/biosynthesis , Kidney/blood supply , Reperfusion Injury/prevention & control , Animals , HSP70 Heat-Shock Proteins/physiology , Immunohistochemistry , Kidney/pathology , Kidney/physiology , Male , Proliferating Cell Nuclear Antigen/analysis , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction
3.
J Clin Endocrinol Metab ; 90(6): 3367-70, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15657368

ABSTRACT

Prader-Willi syndrome (PWS) is the most common form of syndromic obesity associated with hyperphagia. Because ghrelin stimulates gastric motility in rodents, and PWS patients have 3- to 4-fold higher fasting plasma ghrelin concentrations than normal subjects, we hypothesized that hyperphagia associated with PWS may be partly explained by rapid gastric emptying due to the increased gastric motility caused by ghrelin. We determined gastric emptying times (GETs) and measured ghrelin levels in 11 PWS children and 11 age-, sex-, and body mass index-matched controls using a standard meal containing [(99m)Tc]diaminetriaminepentacetate. Median plasma ghrelin levels before (precibum) and after the GET study were higher in PWS patients than in controls (P = 0.004 and P = 0.001, respectively). Median percent gastric retentions at 90 min after the standard meal were 57.1% (range, 34.0-83.2%) in PWS patients and 40.2% (range, 27.2-60.2%) in controls (P = 0.03). In particular, precibum ghrelin concentrations were not significantly correlated with the rate of gastric emptying in PWS patients (P = 0.153; r = 0.461) or controls (P = 0.911; r = 0.048). Our results show that gastric emptying in PWS is reduced despite higher ghrelin levels, and that the voracious appetite associated with PWS is related to another mechanism.


Subject(s)
Gastric Emptying/physiology , Peptide Hormones/blood , Prader-Willi Syndrome/blood , Prader-Willi Syndrome/physiopathology , Adolescent , Body Height , Body Weight , Child , Female , Ghrelin , Humans , Male , Reference Values
4.
J Clin Endocrinol Metab ; 89(8): 3885-9, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15292322

ABSTRACT

Ghrelin is a GH-releasing acylated peptide found in the stomach and a centrally acting food intake stimulator. Prader-Willi syndrome (PWS) is a genetic disorder characterized by a voracious appetite and increased fasting ghrelin levels. In this report we describe 24-h ghrelin profiles in PWS children (n = 5) and compare these with age, sex, and body mass index (BMI)-matched controls (n = 5). A 3- to 4-fold increase in ghrelin levels was found in PWS over a 24-h period, compared with controls (P < 0.001). Interestingly, there was a greater tendency for the up-regulation of ghrelin level in lean PWS than in obese PWS. To confirm this finding, we measured fasting ghrelin levels in 39 patients with PWS. Inverse correlations were found between plasma ghrelin levels and the following: age (r = -0.408, P = 0.005), BMI (r = -0.341, P = 0.017), percentage of the ideal weight for age (r = -0.382, P = 0.008), and BMI percentile (r = -0.311, P = 0.027). Our data show that there may be a suppressive (or up-regulating) controlling mechanism of ghrelin secretion in obese (or lean) PWS children. We hope that our data may further explain the mechanisms underlying the insatiable appetite and obesity characteristic of PWS.


Subject(s)
Aging/blood , Body Mass Index , Circadian Rhythm , Fasting/blood , Peptide Hormones/blood , Prader-Willi Syndrome/blood , Prader-Willi Syndrome/pathology , Adolescent , Case-Control Studies , Child , Female , Ghrelin , Humans , Male
5.
Ren Fail ; 24(5): 567-75, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12380901

ABSTRACT

Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children worldwide. Shiga toxin (Stx) associated HUS, the most common type, is now known to be caused by Escherichia coli O157:7, which produces Stxl or the more potent, Stx2. Since the renal tubule is the major tissue affected in the course of HUS and Stx2 is known to be toxic to the renal tubular cells (RTC), we attempted to elucidate the mechanism of renal injury in HUS by studying the alteration of cytokines in the RTC evoked by Stx2. cDNA-array is a powerful tool for evaluating changes in the expression of a group of critical genes and also gives insights on the overview of the gene activation. In this study, we purified Stx2 from the E. coli O157:7, which was isolated from a typical diarrhea-associated HUS patient and then tried to compare the cytokine gene expression between the stimulated RTC and un-stimulated RTC using cDNA-array. Our results showed that one third of the examined cytokine genes were up regulated at least twice by the addition of Vtx2. These up-regulated genes represented the chemokines (macrophage related cytokines), fibrosis-related cytokine (TNF, PDGF) and leukemia inhibitory factors. However, the expression of IL-6, one of the pleiotropic cytokines, was significantly decreased and this finding was confirmed by northern analysis. Our results suggest that VT2 up-regulates the pro-inflammatory cytokines and fibrosis prone growth factors in RTC and that the inhibition of the activation of these cytokines may ameliorate the renal tubular injury in the HUS caused by E. coli O157:7.


Subject(s)
Cytokines/drug effects , Cytokines/genetics , Epithelial Cells/drug effects , Escherichia coli O157/pathogenicity , Gene Expression/drug effects , Gene Expression/genetics , Hemolytic-Uremic Syndrome/etiology , Kidney Tubules/drug effects , Shiga Toxin 2/adverse effects , Shiga Toxin 2/pharmacology , Escherichia coli O157/isolation & purification , Hemolytic-Uremic Syndrome/microbiology , Humans , In Vitro Techniques , Oligonucleotide Array Sequence Analysis , Shiga Toxin 2/isolation & purification , Up-Regulation/drug effects , Up-Regulation/genetics
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