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At least 433 records · Page 24Linked to original sources
PubMed2001

Hirschsprung disease in an infant with a contiguous gene syndrome of chromosome 13.

Hirschsprung disease is a developmental disorder resulting from the arrest of the craniocaudal migration of enteric neurons from the neural crest along gastrointestinal segments of variable length; see Behrman [Nelson textbook of pediatrics, 1992:954-956]. It is a heterogeneous disorder in which familial cases map to at least three loci whose function is necessary for normal neural crest-derived cell development. Homozygous mutations in the endothelin-B receptor gene (EDNRB) on 13q22 have been identified in humans and mice with Hirschsprung disease type 2 (HSCR2). The auditory pigmentary disorder, Waardenburg-Shah syndrome, comprises Waardenburg syndrome and Hirschsprung disease and has also been mapped to the EDNRB locus. Hirschsprung disease, malrotation, isochromia, a profound sensorineural hearing loss, and several other anomalies were found in an infant with an interstitial deletion of 13q, suggesting the existence of a contiguous gene syndrome involving developmental genes necessary for the normal growth of the neural crest derivatives of the eye, inner ear, and colon. We report on an additional patient with a deletion in 13q and Hirschsprung disease. Congenital anomalies associated with deletions of the distal long arm of chromosome 13 are sufficiently consistent to suggest a clinical syndrome.

Chromosome Banding↗
PubMed1999

Identification of a new locus for autosomal recessive Charcot-Marie-Tooth disease with focally folded myelin on chromosome 11p15.

Autosomal recessive Charcot-Marie-Tooth disease type 4B (CMT4B) is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. A locus for CMT4B has previously been mapped to chromosome 11q23 in a southern Italian pedigree. We initially excluded linkage in two Tunisian families with CMT4B to chromosome 11q23, demonstrating genetic heterogeneity within the CMT4B phenotype. Subsequently, using homozygosity mapping and linkage analysis in the largest Tunisian pedigree, we mapped a new locus to chromosome 11p15. A maximum two-point lod score of 6.05 was obtained with the marker D11S1329. Recombination events refined the CMT4B locus region to a 5.6-cM interval between markers D11S1331 and D11S4194. The second Tunisian CMT4B family was excluded from linkage to the new locus, demonstrating the existence of at least a third locus for the CMT4B phenotype.

Charcot-Marie-Tooth Disease↗
PubMed2002

OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease.

Dominant optic atrophy (DOA) is the most common form of inherited optic neuropathy. Although heterogeneous, a major locus has been mapped to chromosome 3q28 and the responsible gene, OPA1, was recently identified. OPA1 is a mitochondrial dynamin-related GTPase implicated in the formation and maintenance of the mitochondrial network. To date, 62 mutations have been identified in a total of 201 DOA patients. Most of them (90%) are distributed from exons 8 to 28 with a majority in the GTPase domain (54%). None were found in the alternatively spliced exons 4, 4b, and 5b. Half of them are truncative mutations (50%) with a frequent recurrent allele, c.2708delTTAG. Most missense mutations (81%) cluster within the putative GTPase domain. Various pathogenic mechanisms may play a role in OPA1 DOA. Truncative mutations in the N-terminal region and perhaps missense mutations in the GTPase domain lead to a loss of function of the encoded protein and haplotype insufficiency. However, there is a cluster of truncation mutations in the in C-terminus, a putative dimerization domain, that could act through a dominant negative effect. The findings that OPA1-type DOA, as Leber optic neuropathy, is caused by the impairment of a mitochondrial protein address the question of the vulnerability of the retinal ganglion cell in response to mitochondrial defects.

Animals↗
PubMed1993

RNase protection analyses show high genetic diversity among field isolates of satellite tobacco mosaic virus.

Fifteen field isolates of satellite tobacco mosaic virus (STMV) were collected from wild Nicotiana glauca plants within a 20-km2 area in southern California. Analyses of the entire length of the satellite genomic RNA of each isolate by RNase protection assays showed that there were 10 different genotypes within the 15 isolates, including some with regions of extreme divergence from the STMV type strain. This indicates a very high level of genetic diversity between natural STMV populations. Isolates from adjacent plants (within 3 m) were not always identical, but were more similar than those from more distant locations. Mapping of the genomic sites of heterogeneity revealed that in all cases the 3' half of the genome, which comprises the untranslated region, was more conserved than were the 5' coding regions.

California↗
PubMed1976

Topographical analysis of yeast ribosomal DNA by cleavage with restriction endonucleases.

Yeast ribosomal DNA (rDNA) was digested with the restriction enzymes Hind III, Hind II and a mixture of Hind II and Hind III. The cleavage products were analyzed by electrophoresis on 1.5% agarose gels. Several distinct bands could be observed, which are derived from the redundant ribosomal transcription units. They are superimposed on a rather broad smear of background DNA, representing the heterogenous 'spacer' sequences. From the restriction maps, together with data obtained by partial digestion, a physical map for the ribosomal transcription unit in yeast could be constructed.

DNA↗
PubMed1990

Gene deletions in Japanese patients with Duchenne and Becker muscular dystrophy.

Thirty-eight unrelated Japanese patients with Duchenne and Becker muscular dystrophy (DMD and BMD) have been investigated with the DMD cDNA probes. The 14-kb DMD cDNA was subdivided into 6 subclones and HindIII-digested DNAs were analyzed by Southern blotting. Out of 38 unrelated patients, 14 showed a deletion of one or several of the exon-containing HindIII fragments (36.8%). These corresponded to 50% (9/18) of BMD patients and 25% (5/20) of DMD patients, and the position and extent of deletions were mapped and proved to be more heterogeneous in DMD than in BMD. Both ends of deletions detected in probe 1-2a were common to all six BMD patients without the maintenance of reading frame of messenger RNA, and 5' ends of deletions in probe 5b-7 were also common but maintained in frame in three BMD patients. The phenotypic-specific deletion in Japanese BMD patients has existed in the 5' end of the DMD gene, although its apparently similar deletion produced a wide range of clinical courses (BMD phenotype). There was no tight correlation between clinical severity and presence or absence of deletion in DMD or BMD.

Adolescent↗
PubMed1999

Protein kinase-dependent overexpression of the nuclear protein pirin in c-JUN and RAS transformed fibroblasts.

Signalling via the protein kinase Raf-MEK-ERK pathway is of major importance for transformation by oncogenes. To identify genes affected by inhibition of this pathway, c-JUN transformed rat fibroblasts were treated with a MEK1 inhibitor (PD98059) and subjected to two-dimensional gel electrophoresis after cell lysis. Gene products with expression influenced by MEK1 inhibition were determined by mass spectrometry of fragments from in-gel tryptic digestions. The expression of pirin, a nuclear factor I-interacting protein, was lowered after inhibition of MEK1. Western blot analysis revealed increased expression of pirin in RAS and c-JUN transformed cells in the absence of PD98059. Inhibition of MEK1 also led to reduced expression of alpha-enolase, phosphoglycerate kinase, elongation factor 2 and heterogeneous nuclear ribonucleoprotein A3, the latter two being detected as truncated proteins. In contrast, the level of ornithine aminotransferase was increased. We conclude that inhibition of MEK1 results in major alterations of protein expression in c-JUN transformed cells, suggesting that this pathway is important for oncogene-induced phenotypic changes.

Animals↗
PubMed1997

Genetic variation in the hepatocyte nuclear factor-1 alpha gene in Danish Caucasians with late-onset NIDDM.

Non-insulin-dependent diabetes mellitus (NIDDM) is a phenotypically and genetically heterogeneous disorder. A recent random genome mapping study has localized a locus termed NIDDM2 that maps to the region of chromosome 12 that includes MODY3, one of the three genes responsible for maturity-onset diabetes of the young, a monogenic form of NIDDM characterized by early age of onset and autosomal dominant inheritance. These findings suggest that NIDDM2 and MODY3 may represent different alleles of the same gene. MODY3 has recently been shown to be the gene encoding the transcription factor hepatocyte nuclear factor-1 alpha (HNF-1 alpha) thereby allowing us to determine whether mutations in the HNF-1 alpha gene are present in subjects with late-onset NIDDM. We screened 84 white NIDDM patients of Danish ancestry and found four nucleotide substitutions that changed the sequence of HNF-1 alpha, Ile27-->Leu, Ala98-->Val, Ser487-->Asn and Arg583-->Gln, five nucleotide substitutions that were silent and did not change the amino acid, Leu17, Gly288, Leu459 and Thr515, and five substitutions in the intron regions. The frequencies of the codon 27, 98 and 487 amino acid variants were similar in 245 unrelated NIDDM patients and 242 age-matched control subjects. The Arg583-->Gln mutation was found in 2 of 245 NIDDM patients and in none of the control subjects. Thus, genetic variation in the HNF-1 alpha gene is not a common factor contributing to NIDDM susceptibility in white subjects of Danish ancestry.

Age of Onset↗
PubMed2001

The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies.

On the basis of eight independent quantitative trait loci (QTL) studies of ethanol (alcohol) preference drinking in mice, a meta-analysis was carried out to examine the replicability of QTLs across studies and to enhance the power of QTL detection and parameter estimation. To avoid genetic heterogeneity, we analyzed only studies of mapping populations derived from the C57BL/6 (B6) and DBA/2 (D2) inbred progenitor strains. Because these studies were carried out in five different laboratories, there were substantial differences in testing procedure, data analysis, and especially in the choice of mapping population (BXD recombinant inbred strains, F2, backcross, selected lines, or congenic strains). Despite this, we found several QTLs that were sufficiently robust as to appear consistently across studies given the strengths and weaknesses of the mapping populations employed. These were on Chromosomes (Chrs) 2 (proximal to mid), 3 (mid to distal), 4 (distal), and 9 (proximal to mid). The P value for each of these QTLs, combined across all applicable studies, ranged from 10(-7) to 10(-15), with the additive effect of each QTL accounting for 3-5% of the trait variance extrapolated to an F2 population. Two other QTLs on Chrs 1 (distal) and 11 (mid) were less consistent, but still reached overall significance (P <.0001).

Alcohol Drinking↗
PubMed2004

Common variants within the interleukin 4 receptor alpha gene (IL4R) are associated with susceptibility to osteoarthritis.

Primary osteoarthritis (OA) is a common late-onset arthritis that demonstrates a complex mode of transmittance with both joint-site and gender-specific heterogeneity. We have previously linkage-mapped an OA susceptibility locus to a 12-cM interval at chromosome 16p12.3-p12.1 in a cohort of 146 affected female sibling-pair families ascertained by total hip replacement (female-THR families), with a maximum multipoint LOD score of 1.7. Despite the low LOD score, we were encouraged to investigate this interval further following the report of a linkage to the same interval in an Icelandic pedigree with an early-onset form of hip OA. Using public databases, we searched the interval for plausible candidates and concluded that the gene encoding the interleukin 4 receptor alpha chain (IL4R) was a particularly strong candidate based on its known role in cartilage homeostasis. We genotyped nine common single nucleotide polymorphisms (SNPs) from within IL4R, including six non-synonymous SNPs, in the 146 probands from our female-THR families (stage 1) and in an independent cohort of 310 female-THR cases (stage 2). We compared allele frequencies with those of 399 age-matched female controls. All individuals were UK Caucasians. The minor alleles of two SNPs demonstrated association in both stages, with the most significant association having a P-value of 0.004 with an odds ratio (OR) of 2.1. These two SNPs defined two associated SNP groups. Inheriting a minor SNP allele from both groups was a particular risk factor (OR=2.4, P=0.0008). Our data suggest that functional variants within the IL4R gene predispose to hip OA in Caucasian females.

Aged↗
PubMed1995

Biaxial strain analysis of the porcine aortic valve.

The function of a bioprosthetic heart valve is determined largely by the material properties of the valve cusps. The mechanics of natural and bioprosthetic valve cusps have been studied extensively using uniaxial tensile testing. This type of testing, however, does not duplicate the natural biaxial loading condition. Whole-valve biaxial testing therefore is preferred. The objective of the present study was to investigate the heterogeneity of the valve cusps by mapping out the regional variability of the biaxial strain versus pressure relationship. Whole porcine aortic valves were mounted horizontally, submerged in physiologic saline solution at 37 degrees C, and pressurized in the range of 0 to 130 mm Hg of pressure. The ventricular side of the cusps were marked with black dots and the three-dimensional position of these dots was recorded together with the aortic pressure. By calculating the distance between the dots in the radial and circumferential directions in different regions, the local strain versus pressure relationship was determined. The results showed that the valve cusp material strained by 23% +/- 0.8% in the radial direction and 10.0% +/- 0.5% in the circumferential direction before lock-up. It was also found that while the valve cusp was highly anisotropic in the central region, the basal region was relatively isotropic, and the cusp as a whole was asymmetrical in its distensibility.

Animals↗
PubMed1984

Excess 5'-terminal sequences in the rat nucleolar 28S ribosomal RNA.

The 5'-termini of purified rat liver nucleolar and cytoplasmic 28S ribosomal RNA (rRNA) are precisely located within the homologous rDNA sequence by S1 nuclease protection mapping using an appropriate rDNA restriction fragment. The 5'-termini of nucleolar 28S rRNA are heterogeneous in length. The bulk of the nucleolar 28S rRNA map within two CTC motifs in rDNA located in the internal transcribed spacer 2 at the 50-60 and 5-15 bp upstream from the site of the homogeneous 5'-terminus of the cytoplasmic 28S rRNA. These results provide direct proof that nucleolar 28S rRNA molecules contain excess sequences at their 5'-termini and require further processing to generate the mature cytoplasmic 28S rRNA.

Animals↗
PubMed1986

A biochemical comparison of glucosephosphate isomerase isozymes from Trypanosoma cruzi.

The glucosephosphate isomerase (D-glucose-6-phosphate Ketol-isomerase, EC 5.3.1.9) isozymes of Trypanosoma cruzi were characterized with respect to their native and subunit molecular size, isoelectric point and in vitro thermostability. The molecular weight data are consistent with a dimeric enzyme structure. The apparent native and subunit size homogeneity and differences in pI values imply that the electrophoretic mobility differences of isozymes in native gels are determined by their molecular charge. Minor differences in peptide maps indicate the existence of some heterogeneity in the primary structure of the isozymes. The stability of triple-banded glucosephosphate isomerase electrophoretic profiles was confirmed, supporting the view that these phenotypes represent non-interconvertible enzyme species.

Animals↗
PubMed1988

Molecular cloning and characterization of the met2 gene from Ascobolus immersus.

We have cloned the met2 gene from Ascobolus immersus by heterologous hybridization with the MET2 gene of Saccharomyces cerevisiae. This gene codes for the homoserine O-transacetylase, one of the methionine biosynthetic enzymes. The complete nucleotide sequence of a 2910-bp DNA fragment carrying the met2 gene has been determined. The gene contains a 165-bp intron which is similar in structure to other fungal introns. The deduced amino acid (aa) sequence (518 aa residues; Mr of 57726) shows three domains with a significant level of homology with the corresponding yeast protein. Northern-blot analysis reveals at least two transcripts (2.4 and 2.1 kb) probably due to transcription termination heterogeneity, as suggested by S1-mapping experiments. Polymorphism has been observed in the met2 gene flanking regions of Ascobolus strains from two different stocks.

Acetyltransferases↗
PubMed2006

Measurement of the surface energy of lubricated pharmaceutical powders by inverse gas chromatography.

The objective of the study was to determine whether lubrication of pharmaceutical powders with magnesium stearate (MgSt) results in a change in the surface energy of the powder, and to assess whether surface energy changes, if any, are correlated to lubricant concentration and blend time. The surface energies of microcrystalline cellulose (MCC), lactose, and blends of each material with MgSt, prepared at a range of concentrations and blending times were measured using inverse gas chromatography. The physical distribution of MgSt in the blend was mapped by energy dispersive spectrometry. Overall, there was a reduction in the dispersive surface energy of MCC-MgSt blends with increase in MgSt concentration, that was attributed to increasing coverage of the high-energy sites on microcrystalline cellulose by magnesium stearate. MgSt concentration had a larger effect on dispersive energy than the blending time of the powder with lubricant. X-ray maps of blend samples indicated a heterogeneous distribution of the lubricant in the blend and on the excipient particles. Measurement of the specific component of surface energy indicated that MgSt interacts with excipient powders through non-specific forces rather than acid-base interactions. No distinction among lactose-MgSt blends could be made on the basis of dispersive energy because of similar surface energies of the native materials.

Cellulose↗
PubMed2005

Spatial distribution of coke residues in porous catalyst pellets analyzed by field-cycling relaxometry and parameter imaging.

The distribution of coke residues inside porous catalyst pellets was investigated on the molecular as well as the macroscopic scale. The presence of coke on the pore surface affects the relaxation properties of adsorbed liquid species; these were determined by field-cycling relaxometry for different polar and nonpolar liquids in metal-doped and metal-free catalyst carrier materials. The presence of metal in the Al2O3 matrix had only a minor influence on the dispersion behavior, while the interaction of the adsorbates with the coke layer leads to considerable changes in the relaxation times at low Larmor frequencies. Lowering the temperature to well below the bulk freezing point of dimethyl sulfoxide resulted in a slightly stronger frequency dependence of T1. Not only relaxation times but also the diffusion coefficient is affected by the presence of coke residues in the pores. For macroscopically heterogeneous samples, they offer the possibility to generate maps of the local coke concentration by introducing appropriate filters into NMR imaging sequences. High-temperature regeneration of coked catalysts leads to such heterogeneous distributions which is visualized by T1 parameter imaging.

Adsorption↗
PubMed2003

Cryo-negative staining reveals conformational flexibility within yeast RNA polymerase I.

The structure of the yeast DNA-dependent RNA polymerase I (RNA Pol I), prepared by cryo-negative staining, was studied by electron microscopy. A structural model of the enzyme at a resolution of 1.8 nm was determined from the analysis of isolated molecules and showed an excellent fit with the atomic structure of the RNA Pol II Delta4/7. The high signal-to-noise ratio (SNR) of the stained molecular images revealed a conformational flexibility within the image data set that could be recovered in three-dimensions after implementation of a novel strategy to sort the "open" and "closed" conformations in our heterogeneous data set. This conformational change mapped in the "wall/flap" domain of the second largest subunit (beta-like) and allows a better accessibility of the DNA-binding groove. This displacement of the wall/flap domain could play an important role in the transition between initiation and elongation state of the enzyme. Moreover, a protrusion was apparent in the cryo-negatively stained model, which was absent in the atomic structure and was not detected in previous 3D models of RNA Pol I. This structure could, however, be detected in unstained views of the enzyme obtained from frozen hydrated 2D crystals, indicating that this novel feature is not induced by the staining process. Unexpectedly, negatively charged molybdenum compounds were found to accumulate within the DNA-binding groove, which is best explained by the highly positive electrostatic potential of this region of the molecule, thus, suggesting that the stain distribution reflects the overall surface charge of the molecule.

Binding Sites↗