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PubMed2005

Evidence for shutter-speed variation in CR bolus-tracking studies of human pathology.

The standard pharmacokinetic model for the analysis of MRI contrast reagent (CR) bolus-tracking (B-T) data assumes that the mean intracellular water molecule lifetime (tau(i)) is effectively zero. This assertion is inconsistent with a considerable body of physiological measurements. Furthermore, theory and simulation show the B-T time-course shape to be very sensitive to the tau(i) magnitude in the physiological range (hundreds of milliseconds to several seconds). Consequently, this standard model aspect can cause significant underestimations (factors of 2 or 3) of the two parameters usually determined: K(trans), the vascular wall CR transfer rate constant, and v(e), the CR distribution volume (the extracellular, extravascular space fraction). Analyses of animal model data confirmed two predicted behaviors indicative of this standard model inadequacy: (1) a specific temporal pattern for the mismatch between the best-fitted curve and data; and (2) an inverse dependence of the curve's K(trans) and v(e) magnitudes on the CR dose. These parameters should be CR dose-independent. The most parsimonious analysis allowing for realistic tau(i) values is the 'shutter-speed' model. Its application to the experimental animal data essentially eliminated the two standard model signature inadequacies. This paper reports the first survey for the extent of this 'shutter-speed effect' in human data. Retrospective analyses are made of clinical data chosen from a range of pathology (the active multiple sclerosis lesion, the invasive ductal carcinoma breast tumor, and osteosarcoma in the leg) that provides a wide variation, particularly of K(trans). The signature temporal mismatch of the standard model is observed in all cases, and is essentially eliminated by use of the shutter-speed model. Pixel-by-pixel maps show that parameter values from the shutter-speed analysis are increased by more than a factor of 3 for some lesion regions. This endows the lesions with very high contrast, and reveals heterogeneities that are often not seen in the standard model maps. Normal muscle regions in the leg allow validation of the shutter-speed model K(trans), v(e), and tau(i) magnitudes, by comparison with results of previous careful rat leg studies not possible for human subjects.

Adult↗

PubMed1981

Multiple mRNAs are generated from the chicken lysozyme gene.

We have determined the DNA sequence of a 770 bp Pst 1 fragment containing 450 nucleotides of the 5' flanking region of the chicken lysozyme gene. S1-nuclease mapping was performed to localize the 5' end of nuclear RNA containing lysozyme-specific sequences and of the mRNA. We present evidence that the 5' noncoding region of the chicken lysozyme mRNA is heterogeneous in length. The 5' termini of the different nRNAs map 29, 31 and 53 nucleotides upstream from their common initiation codon. The 5' ends of lysozyme-specific nuclear RNAs map at positions similar to that of the mRNA. AT-rich regions and sequences similar to the E. coli RNA polymerase recognition sequence are found around 30 and 70 nucleotides upstream from each of these 5' termini. The AT-rich regions differ, however, from the canonical Goldberg-Hogness box in that they do not contain the extremely conserved TATA sequence motif. Sequence comparison at the 5' end of the lysozyme, conalbumin and ovalbumin genes reveals only one region of partial homology, 140 nucleotides upstream from the mRNA start sites.

Animals↗

PubMed1991

Characterization of the memory gene dunce of Drosophila melanogaster.

The dunce (dnc) gene of Drosophila melanogaster encodes cAMP phosphodiesterase (PDEase) and is required for learning/memory and female fertility. The gene is structurally complex, demonstrated in part by Northern blotting experiments which detected multiple RNAs ranging in size from 4.2 to 9.6 kb (1 kb = 10(3) bases or base-pairs). To characterize these RNAs and to understand their sequence heterogeneity, we isolated and analyzed 29 new and independent cDNA clones representing the dnc RNAs. Restriction mapping, hybridization analysis and sequence determination of these cDNA clones and the corresponding genomic exons resolved these into six different classes. Exons defined by the cDNA clones are distributed over more than 148 kb of genomic DNA, with some exons being used alternatively among the RNAs. The RNAs are transcribed from at least three initiation sites: two of these were mapped by parallel S1-nuclease and primer extension experiments. In addition, some of the heterogeneity is generated by using varying lengths of a 3'-untranslated trailer sequence. Altogether, the results indicate that the size and sequence heterogeneity of dnc transcripts results from transcription initiation at multiple sites, alternative splicing, and processes which generate different 3' ends. The existence of multiple protein products is suggested by the alternative use of exons which code for portions of the open reading frame. The protein variation potentially includes N-terminal differences coded for by transcript-specific 5' exons and internal differences arising from the optional inclusion of a 39 base-pair exon and from the alternative use of two 3' splice sites separated by six base-pairs. Expression of a cDNA clone in yeast containing a large portion of the open reading frame produced cAMP PDEase activity identical in properties to the Drosophila enzyme affected by the dnc mutation. The results suggest that the remarkable structural complexity of dnc may reflect an intricate control of the spatial and/or temporal expression of various isoforms of cAMP PDEase.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2005

QTL mapping in a mouse model of cardiomyopathy reveals an ancestral modifier allele affecting heart function and survival.

The progression from myocardial hypertrophy to heart failure is a complex process, involving genetic and environmental factors. Elucidating the genetic components contributing to heart failure has been difficult, largely because of the heterogeneity of human populations. We have employed a strategy to map genetic loci that modify the heart failure phenotype in a transgenic mouse model of cardiomyopathy caused by cardiac-specific overexpression of calsequestrin. Strain-specific differences in both cardiac function and survival are observed when the transgene is moved into different inbred mouse strains. We have previously reported linkage results from mapping in reciprocal backcrosses between C57/BL6 (BL6) and DBA/2J (DBA) and a backcross between DBA/AKR and AKR. Here we report the results of a genome-wide linkage scan in the reciprocal backcross between DBA/AKR and DBA. We identified one novel locus on Chromosome (Chr) 18 that affects heart function and a second on Chr 3 that shows significant linkage to both survival and heart function. Intriguingly, the Chr 3 allele of AKR shows a susceptibility effect on phenotype, whereas the overall effect of the AKR genetic background is protective. The Chr 3 locus also completely overlaps the Hrtfm2 locus, which was previously mapped in crosses between DBA and BL6. Mapping the same QTL in two different crosses allowed us to use ancestral haplotypes to narrow the candidate gene interval from 9 to 2 Mb. Identification of the genes at these QTLs in the mouse will provide novel candidate genes that can be evaluated for their role in human heart failure.

Alleles↗

PubMed1997

Mapping pathophysiological features of breast tumors by MRI at high spatial resolution.

Magnetic resonance imaging (MRI) is a noninvasive method that reveals anatomical details in vivo and detects lesions for diagnosis. Although standard breast MRI cannot clearly delineate breast cancer, contrast-enhanced MRI enables the detection of breast masses with high sensitivity. Dynamic studies demonstrated that malignant lesions were characterized by a faster signal enhancement rate than benign ones. Dynamic MRI of human breast cancer in mice revealed high heterogeneity in the distribution of contrast-enhanced curves and derived pathophysiological features, indicating the importance of high spatial resolution. With clinical MRI, it is difficult to achieve simultaneously high spatial and temporal resolution. In previous dynamic studies, the emphasis was on high temporal resolution and mainly empiric analyses. We describe here a new model-based method that optimizes spatial resolution by using only three time points, and yet characterizes tumor heterogeneity in terms of microvascular permeability and extracellular fraction. Mapping these pathophysiological features may aid diagnosis and prognosis assessment, while the high spatial resolution may improve the capacity to detect smaller lesions. The method was tested in human breast tumors implanted in mice and in a limited number of benign and malignant breast lesions of patients.

Animals↗

PubMed1992

Genetic marker study of dentinogenesis imperfecta.

DGI-II has been linked to the group specific component (Gc) on 4q and to interferon induced protein 10 (INP10) on 4q. We studied a three generation family with DGI-II along with a four generation DGI-II family to more precisely place DGI-II in the existing genetic map of 4q and to determine if genetic heterogeneity existed between various DGI-II families. Affected family members had brownish discoloration of the teeth, enamel fracturing and radiographic evidence of coronal and radicular pulp chamber obliteration. Thirteen polymorphic markers on 4q were studied including D4S35, D4S1, ALB, Gc, MGSA, AR, INP10, ADH3, FGFB, EGF, IL2, IF, and MNS. Gc and MNS blood group antigen typing were done using commercial SERA. Restriction fragment length polymorphism analysis using Southern blotting was done on the remaining markers. Pairwise linkage analysis was performed using the procedures of Morton. Tight linkage between DGI-II and eleven genetic markers, including Gc and EGF, was excluded. The tightest linkage with DGI-II was identified with the probe INP10 at theta = 0.0 with lod = +3.91. However, INP10 RFLP differences were detected between the families, such that DGI-II correlated with different alleles in each family. Results from this study demonstrated that DGI-II may possibly arise from more than one genetic mutation.

Alleles↗

PubMed2006

Genome-wide linkage scan for prostate cancer susceptibility genes in men with aggressive disease: significant evidence for linkage at chromosome 15q12.

Epidemiological and twin studies have consistently demonstrated a strong genetic component to prostate cancer (PCa) susceptibility. To date, numerous linkage studies have been performed to identify chromosomal regions containing PCa susceptibility genes. Unfortunately, results from these studies have failed to form any obvious consensus regarding which regions are most likely to contain genes that may contribute to PCa predisposition. One plausible explanation for the difficulty in mapping susceptibility loci is the existence of considerable heterogeneity in the phenotype of PCa, with significant variation in clinical stage and grade of disease even among family members. To address this issue, we performed a genome-wide linkage scan on 71 informative families with two or more men with aggressive PCa. When only men with aggressive PCa were coded as affected, statistically significant evidence for linkage at chromosome 15q12 was detected (LOD=3.49; genome-wide p=0.005). Furthermore, the evidence for linkage increased when analyses were restricted to Caucasian-American pedigrees (n=65; LOD=4.05) and pedigrees with two confirmed aggressive cases (n=42, LOD=4.76). Interestingly, a 1-LOD support interval about our peak at 15q12 overlaps a region of suggestive linkage, 15q11, identified by a recent linkage study on 1,233 PCa families by the International Consortium for Prostate Cancer Genetics. Using a more rigid definition of PCa in linkage studies will result in a severe reduction in sample sizes available for study, but may ultimately prove to increase statistical power to detect susceptibility genes for this multigenic trait.

Alleles↗

PubMedDate not supplied

A sensorineural progressive autosomal recessive form of isolated deafness, DFNB13, maps to chromosome 7q34-q36.

Deafness is the most frequent sensorineural defect in children. The vast majority of the prelingual forms of isolated deafness are highly genetically heterogeneous with an autosomal recessive mode of inheritance. Using linkage analysis, we have mapped the gene responsible for a severe progressive sensorineural hearing loss, DFNB13, segregating in a large consanguineous family living in an isolated region in northern Lebanon. A maximum lod score of 4.5 was detected for markers D7S661-D7S498. Recombination events and homozygosity mapping by descent define a 17 cM gene interval in the chromosome region 7q34-q36, between the markers D7S2468/D7S2505, on the proximal side, and D7S2439, on the distal side.

Chromosome Mapping↗

PubMed2000

A new locus for autosomal recessive limb-girdle muscular dystrophy in a large consanguineous Tunisian family maps to chromosome 19q13.3.

Autosomal recessive limb-girdle muscular dystrophies represent a genetically heterogeneous group of diseases characterized by a progressive involvement of skeletal muscles. They show a wide spectrum of clinical courses, varying from very mild to severe. Eight loci responsible for autosomal recessive limb-girdle muscular dystrophies have been mapped and six defective genes identified. In this study, we report the clinical data, muscle biopsy findings and results of genetic linkage analysis in a large consanguineous Tunisian family with 13 individuals suffering from autosomal recessive limb-girdle muscular dystrophy. Clinical features include variable age of onset, proximal limb muscle weakness and wasting predominantly affecting the pelvic girdle, and variable course between siblings. CK rate was usually high in younger patients. Muscle biopsy showed dystrophic changes with normal expression of dystrophin and various proteins of the dystrophin-associated protein complex (sarcoglycan sub-units, dystroglycan, and sarcospan). Genetic linkage analysis excluded the known limb-girdle muscular dystrophies loci as well as ten additional candidate genes. A maximum LOD score of 4.36 at θ=0.00 was obtained with marker D19S606, mapping this new form of autosomal recessive limb-girdle muscular dystrophy to chromosome 19q13.3.

Adolescent↗

PubMed1985

Analysis of the major transcripts encoded by the long repeat of human cytomegalovirus strain AD169.

In this report, we describe the size and kinetics of appearance of RNAs from the long repeat of human cytomegalovirus. The most abundant RNA from this region was a 2.7-kilobase (kb) species that was detected throughout the infection and was most abundant at 27 and 72 h after infection. The 2.7-kb RNA was the only major species detected with a probe that included the terminus of the long repeat and the heterogeneous L-S junction region. Other transcripts were detected with probes from the internal portion of the long repeat, including an immediate-early RNA of 1.3 kb, early and late RNAs of 1.2 kb, and minor late transcripts of 4.4, 3.6, 3.3, and 1.8 kb. S1 nuclease and exonuclease VII protection analyses of RNA from immediate-early, early, midpoint, and late times in the infection indicated that the major 2.7-kb RNA was not spliced and that the RNA mapped within the long repeat, 1.6 kb from the heterogeneous region. No evidence for temporally regulated changes in transcription initiation, splicing, or choice of 3' end of this RNA was observed. Nuclease protection analysis also demonstrated that the second most abundant late RNA from this region, the 1.2-kb species, was not spliced and had the same polarity as the 2.7-kb RNA. The 1.2-kb also mapped entirely within the long repeat, with its 3' terminus 1.7 kb upstream from the 5' terminus of the 2.7-kb RNA.

Base Sequence↗

PubMed1998

Ultraspatially-resolved synchrotron infrared microspectroscopy of plant tissue in situ.

Routine use of 6 microm or 12 microm apertures with synchrotron microspectroscopy provide good spectra without excessive co-addition of scans. 100% mapping by stepping in pixel sized increments reveals chemical heterogeneity within cellular dimensions. The brightness of the synchrotron source and the absence of thermal noise compared to a conventional thermal (globar) source yields favorable signal-to-noise operation. The nondivergent characteristics of the source result in minimal loss of radiation at the aperture, hence, spatial resolution approaches the diffraction limit. Details of cellular dimensions are then localized within any maps produced and individual spectra obtained from adjacent pixels clearly shows the striking difference in chemistry even within a microscopic vicinity. In this report the mapping of plant tissue with the synchrotron is contrasted to previous lower spatial resolution mapping experiments done with the globar on similar materials using interpolation between separated sampling spots and larger apertures.

Absorption↗

PubMed2005

A novel locus for autosomal dominant non-syndromic deafness, DFNA53, maps to chromosome 14q11.2-q12.

BACKGROUND: Non-syndromic hearing loss is among the most genetically heterogeneous traits known in humans. To date, at least 50 loci for autosomal dominant non-syndromic sensorineural hearing loss (ADNSSHL) have been identified by linkage analysis. OBJECTIVE: To report the mapping of a novel autosomal dominant deafness locus on the long arm of chromosome 14 at 14q11.2-q12, DFNA53, in a large multigenerational Chinese family with post-lingual, high frequency hearing loss that progresses to involve all frequencies. RESULTS: A maximum multipoint LOD score of 5.4 was obtained for marker D14S1280. The analysis of recombinant haplotypes mapped DFNA53 to a 9.6 cM region interval between markers D14S581 and D14S1021. Four deafness loci (DFNA9, DFNA23, DFNB5, and DFNB35) have previously been mapped to the long arm of chromosome 14. The critical region for DFNA53 contains the gene for DFNA9 but does not overlap with the regions for DFNB5, DFNA23, or DFNB35. Screening of the COCH gene (DFNA9), BOCT, EFS, and HSPC156 within the DFNA53 interval did not identify the cause for deafness in this family. CONCLUSIONS: Identifying the DFNA53 locus is the first step in isolating the gene responsible for hearing loss in this large multigeneration Chinese family.

Adolescent↗

PubMed2005

Posterior polar cataract: genetic analysis of a large family.

Congenital cataracts are clinically and genetically heterogeneous. Loci for autosomal dominant posterior polar cataracts have been mapped to chromosomes 1p36, 11q22-q22.3, 16q22, and 20p12-q12. We investigated a large four-generation family with 20 individuals affected with congenital posterior polar cataracts. After exclusion of known loci for posterior polar cataracts, a genome-wide screen was conducted. In this family, we mapped dominant congenital posterior polar cataracts to chromosome 10q24. On haplotype analysis, we identified an 11-cM interval between loci D10S1680 and D10S467, which included the PITX3 gene. On sequencing the coding region of PITX3, we found a 17-base-pair duplication in exon 4. Although the same genotype was described in a family with ASMD and cataracts, the common phenotype of this mutation is probably posterior polar cataract; a modifier gene is presumed to cause anterior segment abnormalities in the previously described patients. The same mutation was recently identified in four families with congenital cataracts. This study provides further evidence of genetic heterogeneity of autosomal dominant posterior polar cataract.

Amino Acid Sequence↗

PubMed1994

Bootstrapping in human genetic linkage.

Linkage analysis of discrete Mendelian traits has made a major contribution to the mapping of the human genome. However, in more complex situations, particularly Mendelian disorders showing locus heterogeneity, linkage results have sometimes been misleading. The bootstrap confidence interval provides an assessment of the goodness of fit of the data to the genetic model and the presence of heterogeneity can inflate the confidence interval indicating that the fit is poor. The loss in statistical power and the potential unreliability of linkage analyses based on small samples or subsamples of pedigree material is explored and illustrated by using simulated data and also real data on 37 families affected by the heterogeneous disorder, tuberous sclerosis.

Chromosome Mapping↗

PubMed1995

A genetic map of chromosome 11q, including the atopy locus.

Atopy is a common and genetically heterogeneous syndrome predisposing to allergic asthma and rhinitis. A locus linked to the atopy phenotype has been shown to be present on chromosome 11q12-13. Linkage has only been seen in maternally derived alleles. We have constructed a genetic linkage map of the region, using 15 markers to span approximately 27 cM, and integrate previously published maps. Under a model of maternal inheritance, the atopy locus is placed within a 7-cM interval between D11S480 and D11S451. The interval contains the important candidate gene FCERIB.

Alleles↗

PubMed2000

Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3-independent mechanism.

Defects in a triad of organelles (melanosomes, platelet granules, and lysosomes) result in albinism, prolonged bleeding, and lysosome abnormalities in Hermansky-Pudlak syndrome (HPS). Defects in HPS1, a protein of unknown function, and in components of the AP-3 complex cause some, but not all, cases of HPS in humans. There have been 15 inherited models of HPS described in the mouse, underscoring its marked genetic heterogeneity. Here we characterize a new spontaneous mutation in the mouse, cappuccino (cno), that maps to mouse chromosome 5 in a region conserved with human 4p15-p16. Melanosomes of cno/cno mice are immature and dramatically decreased in number in the eye and skin, resulting in severe oculocutaneous albinism. Platelet dense body contents (adenosine triphosphate, serotonin) are markedly deficient, leading to defective aggregation and prolonged bleeding. Lysosomal enzyme concentrations are significantly elevated in the kidney and liver. Genetic, immunofluorescence microscopy, and lysosomal protein trafficking studies indicate that the AP-3 complex is intact in cno/cno mice. It was concluded that the cappuccino gene encodes a product involved in an AP-3-independent mechanism critical to the biogenesis of lysosome-related organelles. (Blood. 2000;96:4227-4235)

Adaptor Protein Complex alpha Subunits↗

PubMed2006

Water diffusion heterogeneity index in the human brain is insensitive to the orientation of applied magnetic field gradients.

The alpha diffusion-weighted imaging (DWI) method was developed to study heterogeneous water diffusion in the human brain using magnetic resonance imaging (MRI). An advantage of this model is that it does not require an assumption about the shape of the intravoxel distribution of apparent diffusion rates, and it has a calculable relationship to this distribution. The alpha-DWI technique is useful for detecting microstructural tissue changes associated with brain tumor invasion, and may be useful for directing therapy to invading tumor cells. In previous work, alpha-DWI was performed with magnetic field gradients applied along a single direction in order to avoid artificially introducing a source of heterogeneity to the decay. However, it is known that restricted diffusion is anisotropic in the brain, and the alpha-DWI method must take this into account to be complete. In this work the relationship between the applied magnetic field gradients and the fitted stretched-exponential model parameters was studied in the human brain. It was found the distributed diffusion coefficient (DDC) varies with the direction of applied gradients, while the heterogeneity index alpha is relatively direction-insensitive. It is proposed that in clinical use, maps of alpha can be created using diffusion-weighting gradients applied in a single direction that reflect the tissue heterogeneity.

Algorithms↗

PubMed2002

Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease.

OBJECTIVES: To formulate an equation for fine mapping of disease loci under complex conditions and determine the marker-disease distance in a specific case using this equation. METHODS: Lewontin's linkage disequilibrium (LD) measure D' was used to formulate an equation for mapping disease genes in the presence of phenocopies, locus heterogeneity, gene-gene and gene-environment interactions, incomplete penetrance, uncertain liability and threshold, incomplete initial LD, natural selection, recurrent mutation, high disease allele frequency and unknown mode of inheritance. This equation was then used to determine the distance between a marker ( epsilon 4 within the apolipoprotein E gene, APOE) and Alzheimer's disease (AD) loci using published data. RESULTS: An equation was formulated for mapping disease genes under the above conditions.If these conditions are present but ignored, then recombination fraction theta between marker and disease loci will be either overestimated or estimated with little bias. Therefore, an upper limit of theta can be obtained. AD has been found to be associated with the marker allele epsilon 4 in Africans, Asians, and Caucasians. This suggests that the AD- epsilon 4 allelic LD predates the divergence of peoples occurring 100 000 years ago. With the age of AD- epsilon 4 allelic LD so estimated, the maximal distance was calculated to be 23.2 kb (mean 5.8 kb). CONCLUSIONS: (1) A method is developed for LD mapping of susceptibility genes. (2) A mutation within the APOE gene itself, among others, is responsible for the susceptibility to AD, which is supported by recent evidence from studies using transgenic mice.

Alzheimer Disease↗