摘要:

The homeobox, a 60-amino acid-encoding DNA sequence, originally discovered in the genome of the fruit flyDrosophila,was subsequently identified throughout the three kingdoms of multicellular organisms. Homeobox-containing genes encode DNA-binding proteins that regulate gene expression and control various aspects of morphogenesis and cell differentiation. In particular, theHoxfamily of clustered homeobox genes plays a fundamental role in the morphogenesis of the vertebrate embryo, providing cells with regional information along the main body axis. The nonclustered or divergent homeobox genes include a large number of genes scattered throughout the genome that, nevertheless, can be organized in distinct families based on their homologies and functional similarities. This review will provide the reader with a brief overview on some recent studies aimed at understanding the functional role of homeobox genes in normal mammalian development as well as their involvement in congenital malformations and oncogenesis.Abbreviations: ES,embryonic stem;NCC,neural crest cells;GPP,ground patterning program;WS,Waardenburg syndrome;AML,acute myeloid leukemia;ALL,acute lymphoblastic leukemia

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Hyperphenylalaninemia (HPA) resulting from deficient activity of phenylalanine hydroxylase (PAH) is caused by mutations in the humanPAHgene (McKusick 261600). Herein, we report a noninvasive method to:1) estimate whole-body phenylalanine oxidation in patients with HPA and2) compare effects of mutant genotypes on phenotypes. We used oral L-[1-13C]phenylalanine as a substrate and measured13CO2formation in the first hour as an index of phenylalanine oxidation rates in:1) patients with PKU (n= 6), variant phenylketonuria (PKU) (n= 7) and non-PKU HPA (n= 4);2) obligate heterozygotes (n= 18); and3) controls (n= 8). PAH mutations were identified by PCR, denaturing gradient gel electrophoresis, and DNA sequencing. Phenylalanine oxidation rates demonstrated a gene dosage effect; oxidation in heterozygotes was intermediate between probands and controls. The three classes of HPA had different mean oxidation rates (PKU < variant PKU < non-PKU HPA). Thein vivophenotype (HPA class or whole-body oxidation rate) did not always correspond to prediction fromin vitroexpression analysis of the mutation effect on enzyme activity. The findings indicate that thein vivometrical trait (phenylalanine oxidation rate) is not a simple equivalent of phenylalanine hydroxylation activity (unit of protein phenotype) and, as expected, is an emergent property under the control of more than thePAHlocus.Abbreviations: HPA,hyperphenylalaninemia;PAH,phenylalanine hydroxylase enzyme;PAH,human phenylalanine hydroxylase gene;PKU,phenylketonuria

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The gene for Menkes disease, an X-linked disorder of copper transport, has recently been identified and shown to encode a copper-transporting P-type ATPase. The macular mutant mouse has been proposed as an animal model for Menkes disease. In the present study, we report the finding of a missense mutation in the mottled gene of the macular mouse. A single base change, T to C, at nucleotide position 4223, is predicted to result in an amino acid change from serine to proline at residue 1382 in the eighth transmembrane domain. This mutation differs from the 6-bp deletion we find in brindled cDNA. With validation of macular as an animal model of Menkes disease, we compared mottled gene expression in the intestine, kidney, and brain of macular and normal mice. In Northern analyses an 8.3-kb transcript was detected in the intestine, kidney, and brain of both normal and macular mice, with the level of transcript in macular approximately 80% that of normal.In situhybridization studies revealed that the mottled gene was clearly expressed in intestinal epithelial cells, Paneth cells, and renal proximal tubular cells of both normal and macular mice. In normal brain, mottled gene expression was most intensely observed in the choroid plexus, in Ammon's horn and the dentate gyrus in the hippocampus, in Purkinje cells, and the granular layer of the cerebellum. The intensity and localization of the signals in the brain of macular mice were similar to those of the controls. The distribution of expression of mottled is correlated with cells and tissues showing histopathology or abnormal copper sequestration in macular and other mutants.Abbreviations: MNK,Menkes disease;SSC,sodium citrate-sodium chloride;SSPE,sodium phosphate-sodium chloride-EDTA

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Activating mutations of the Ca2+-sensing receptor (CaR) gene cause autosomal dominant hypoparathyroidism. Functional expression studies have been reported for several mutations, but have produced conflicting results. Thus, the mechanism by which these mutations activate the receptor is unclear. We describe here a new family with autosomal dominant hypoparathyroidism. The mother and three daughters experienced muscle spasms and/or seizures from early childhood. They were treated with oral calcium and vitamin D analogs, and all four patients developed hypercalciuria, nephrocalcinosis, and renal insufficiency. In this family, we identified a heterozygous missense mutation(F612S) involving the extracellular region of the CaR. The mutation cosegregated with disease. It was not present in 50 normal control individuals. We used site-directed mutagenesis to introduce this mutation into the CaR cDNA, and then expressed the mutant receptor in human embryonic kidney(HEK)-293 cells. In these cells, the accumulation of inositol phosphates was measured as a function of extracellular Ca2+concentration. Compared with the wild-type receptor, the mutant receptor showed a left-shift in the concentration-response curve and an increase in the maximal response to high Ca2+concentrations. These effects did not appear to be mediated by changes in levels of receptor expression, as judged by ELISA, or by changes in receptor glycosylation, as judged by Western analysis. We conclude that this CaR mutation causes hypoparathyroidism by a dual increase in receptor sensitivity to extracellular Ca2+and maximal signal transduction capacity.Abbreviations: CaR,Ca2+-sensing receptor;DMEM,Dulbecco's minimal essential medium;WT,wild-type;HEK,human embryonic kidney cell line;IP,inositol phosphate;MDE,mutation detection enhancement

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

We describe a childhood mitochondrial disorder in which the clinical symptoms began and remained confined to the gastrointestinal (GI) system during the first 4 y. Seizures heralded the onset of progressive encephalopathy at age 7. Peripheral neuropathy, retinitis pigmentosa, and neural deafness developed subsequently. Laboratory investigations disclosed elevated levels of plasma lactate, and a muscle biopsy revealed ragged red fibers lacking cytochromecoxidase activity and diminished levels of respiratory chain enzyme complexes. Molecular genetic tests failed to show any of the previously reported pathogenic mitochondrial DNA (mtDNA) mutations. We therefore screened the whole mitochondrial genome by coupling restriction digestions with single-strand conformational polymorphism (SSCP) patterns. We identified a unique SSCP in the segment that encompassed the tRNALysgene, and direct sequencing of this segment revealed a G → A transition at an evolutionarily conserved nucleotide at mtDNA position 8313. This G8313A transition was heteroplasmic in muscle and fibroblasts of the patient, but was absent in the white blood cells and platelets from his maternal relatives. This report illustrates how GI symptoms can be the initial manifestation in a mitochondrial disorder and suggests that mitochondrial dysfunction should be considered in differentials of unexplained chronic GI symptoms, especially when lactic acidosis or other unrelated clinical signs or symptoms are present.Abbreviations: mtDNA,mitochondrial DNA;nDNA,nuclear DNA;GI,gastrointestinal;RRF,ragged red fiber;COX,cytochrome oxidase;SSCP,single-strand conformational polymorphism;MNGIE,mitochondrial neurogastrointestinal encephalomyopathy;MERRF,myoclonic epilepsy with RRF;CIP,chronic intestinal pseudoobstruction;RFLP,restriction fragment length polymorphism

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Catecholamines are a class of neurotransmitters involved in central nervous system autonomic control. Both acute and chronic hypoxia create alterations in ventilation and blood pressure via catecholamine release, although the mechanisms of these alterations are unknown. The enzymes tyrosine hydroxylase(TH) and phenylethanolamineN-methyltransferase (PNMT) catalyze the rate-limiting step in the catecholamine pathway and production of epinephrine, respectively. Both have been colocalized with Fos protein in metabolic mapping studies of the O2-chemosensory pathway of adult and early postnatal rat. Thus, catecholamines are putative neurotransmitters in a subset of second and higher order respiratory neurons. To characterize the effects of prenatal hypoxia on subsequent TH and PNMT gene and protein expression, pregnant rats were placed in moderate hypoxia (10% O2) from gestational d 18 until birth. Northern and Western analyses of dorsal (catecholaminergic/adrenergic cell group 2) and ventral (catecholaminergic/adrenergic cell group 1) medullary tissue of postnatal (P) age P0, P3, P7, P10, and P14 pups were then done to examine changes in TH and PNMT mRNA and protein compared with normoxia-reared controls. Compared with controls, pups exposed to maternal hypoxia during pregnancy had lower levels of TH mRNA and protein at birth in dorsal medulla and higher levels of TH mRNA the first postnatal week in the ventral medulla. Pups that had been hypoxicin uteroshowed significantly lower levels of PNMT protein during the second postnatal week in dorsal medulla than did controls. Prenatal hypoxia-induced changes in levels of enzymes responsible for catecholamine synthesis may later be manifest as developmental deficiencies in neuronal function. This may compromise responses to acute hypoxic challenges during early postnatal life and contribute to autonomic nervous system disorders of the newborn such as apnea and sudden infant death syndrome.Abbreviations: C1/A1,catecholaminergic/adrenergic cell group 1;C2/A2,catecholaminergic/adrenergic cell group 2;G,gestational age;NTS,nucleus tractus solitarii;P,postnatal age;PNMT,phenylethanolamineN-methyltransferase;SIDS,sudden infant death syndrome;SSC,standard sodium citrate;TH,tyrosine hydroxylase;HIF,hypoxia-inducible factor

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Studies of severe hypoxemic events, defined as an arterial oxygen saturation <80% greater than 4 s in spontaneously breathing infants, have been limited. The purpose of our study was to examine the distribution of respiratory events that lead to a fall in oximetrically measured oxygen saturation by using breathing patterns, heart rate, and validated pulse oximetry analysis. A total of 161 hypoxemic events were detected in 18 of 30 premature infants studied. Using an inductive plethysmographic based monitor, a total of 460 h of cardiorespiratory monitor recordings were analyzed. Hypoxemic events were categorized as being the direct result of apnea(duration longer than 15 s) or pauses (duration 4-14 s) with either unchanged or lower end-expiratory lung volumes compared with the preevent breaths. The breaths in the preevent period were analyzed for volume, timing, and thoracoabdominal coordination indices. Forty of the 161 events (25%) were associated with apnea of which 80% (31/40) had a mixed/obstructive basis. Ninety-four of the 161 severe hypoxemic events (58%) were associated with pauses with unchanged end-expiratory lung volume. Twenty-two of the 161 events(14%) showed pauses with lower end-expiratory lung volume. There were 5/161 events (3%) with severe hypoxemia in which no pause was observed. Comparison of the preevent periods in each category showed significant differences for only percent tidal volume from initial calibration and arterial oxygen saturation. Sixty-two percent (100/161) of severe hypoxemic events were preceded by hypopneic values of percent tidal volume. Seventy-five percent(40/161) of these hypoxemic events and their etiology would have gone undetected using respiratory monitoring from impedance pneumograms and ECGs. The varied basis for these events underscores the importance of analyzing detailed respiratory wave forms along with movement-free signal of arterial oxygen saturation and ECG, to formulate appropriate intervention strategies.Abbreviations: EELV,end-expiratory lung volume;Sao2, arterial O2saturation;Sao2G3,Sao2obtained from pulse oximeter;Vt,tidal volume;HR,heart rate;FRC,functional reserve/residual capacity;RIP,respiratory inductive plethysmograph

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

In adult ratsN-methyl-D-aspartate receptor (NMDAR) antagonists increase glucose use and induce a 72-kD heat shock protein (HSP72) expression in limbic system areas that later undergo neuronal necrosis, which have limited the clinical development of these drugs. Dizocilpine maleate (MK-801) and magnesium sulfate (MgSO4) reduce hypoxic-ischemic brain injury in immature animals, but the effects on HSP72 expression and glucose use are unknown. Seven-day-old rats received injections of either vehicle (control), 0.5 or 1.0 mg/kg MK-801, or 2 or 4 mmol/kg MgSO4. Glucose utilization was measured with the deoxyglucose method, 30 min, 48 h, and 4 d after injection. HSP72 immunostaining was evaluated 4 or 24 h after injection. Both doses of MK-801 and 4 mmol/kg MgSO4induced a temporary decrease in glucose use in the posterior cingulate and retrosplenial cortex, the CA1 and CA3 subfields of the hippocampus, the caudoputamen, and the parietal cortex. Doses of 2 mmol/kg MgSO4did not affect glucose use in any structure. Neuronal HSP72 expression was not found in any drug-treated rats. In conclusion, neither MK-801 nor MgSO4increased glucose use in the limbic system and did not induce HSP72 expression, suggesting that NMDAR antagonists lack direct neurotoxicity in the immature brain.Abbreviations: NMDA,N-methyl-D-aspartate;NMDAR,N-methyl-D-aspartate receptor;MK-801,dizocilpine maleate; 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate;HSP72,72-kD heat shock protein;TNT,Tris-NaCl-Tween;2-DG,2-deoxy-D-[U-14C]glucose

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

In adults, spontaneous otoacoustic emissions (SOAE) have shown a considerable frequency stability. In preterm infants, however, the SOAE proved to show an apparent and consistent upward shift of frequency at increasing postconceptional age (PCA). In 25 ears of 14 preterm infants (PCA, 29.1-41.3 wk) a total of 66 SOAE frequencies were monitored, ranging from 1611 to 5774 Hz. All but one of the SOAE frequencies shifted toward higher frequency. The SOAE frequency shift rate in Hertz per week was proportionally constant relative to the SOAE frequency. The mean shift rate was 0.74 ± 0.39%/wk. At increasing PCA, the SOAE frequency shift rate tended to slow down. A linear fit through the data predicted the SOAE frequency to stop at about 45-50-wk PCA. The frequency dependence and time course of the SOAE frequency shift strongly suggest cochlear maturation during the last period of gestation.Abbreviations: OAE,otoacoustic emission;SOAE,spontaneous OAE;CEOAE,click evoked OAE;PCA,postconceptional age;GA,gestational age;FSR,SOAE frequency shift rate;OFSR,overall SOAE frequency shift rate;SPL,sound pressure level

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Leptin, a hormone secreted by adipocytes, is elevated in blood of obese adults. It is unknown whether the concentration is affected by gender, ethnicity, age, or stage of sexual maturation in children. We measured serum leptin levels in 183 children and 27 young adults using a double-antibody ELISA assay. Body fat mass (FM) and percent body fatness (%Fat) were determined by dual-energy x-ray absorptiometry. Correlations for serum leptin with FM,%Fat, and a body mass index were examined. Analyses of covariance were used to determine the effects of gender, ethnicity, and sexual maturation(Tanner stage). We found strong positive correlations (r= 0.56-0.88,p< 0.001) for serum leptin with body mass index,%Fat, and FM, which were gender-dependent (p< 0.001), but unaffected by ethnicity. At each Tanner stage, female subjects had higher serum leptin than male subjects (p< 0.001), and this difference remained significant (p< 0.001) when leptin was normalized for FM. For each gender, the mean leptin/FM ratios were relatively invariant during sexual maturation and no differences were observed between the oldest children(Tanner stage 5) and the young adults. The observation that female subjects have higher mean serum leptin and leptin/FM levels than male subjects at prepubertal ages may suggest that there are gender differences in leptin synthesis, clearance rates, bioactivity, and/or leptin transport.Abbreviations: FM,fat mass;%Fat,percentage fatness;DXA,dual-energy x-ray absorptiometry;LTP, total plasma leptin content;PV,plasma volume;BMI,body mass index

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID