Search PubMed⌕ Search

Biomedical subjects

M R James

Publications and source records attributed to M R James.

At least 37 records · Page 2Linked to original sources
PubMed1998

Bipolar affective disorder partially cosegregates with a balanced t(9;11)(p24;q23.1) chromosomal translocation in a small pedigree.

Analysis of an extended pedigree in which a balanced t(9;11)(p24;q23.1) translocation was found to cosegregate with bipolar affective disorder revealed that five of 11 translocation carriers had bipolar affective disorder and one carrier had unipolar depression. There were no affected individuals in the pedigree without the balanced translocation. We hypothesized that gene(s) or gene regulatory regions disrupted by the translocation might be contributing to the bipolar affective disorder in a dominant fashion. To test this hypothesis, we isolated the derivative chromosome 9 and derivative chromosome 11 in somatic cell hybrids and identified the nearest flanking markers on chromosome 9 (D9S230 and D9S2011E/HRFX3) and chromosome 11 (EST00652 and CRYA2). YAC contigs were constructed in the region of flanking markers for both chromosomes 9 and 11. Chromosome 11 breakpoint was localized within an 8-kb region in a small insert (100 kb) YAC. Chromosome 9 breakpoint was localized within approximately 2 Mb region. Several genes and ESTs including EST00652, CRYA2, DRD2, 5HTR3 on chromosome 11 and VLDLR and SLC1A1 on chromosome 9 were mapped within the vicinity of the breakpoint but were shown not to be disrupted by the translocation breakpoint. Although several possibilities exist regarding the role of the balanced translocation in developing bipolar affective disorder in this pedigree, including a chance cosegregation, identification of a disrupted gene or gene regulatory region with the help of physical mapping resources described in this study may help to identify the presence of a susceptibility gene for this disorder.

Bipolar Disorder↗
PubMed1997

A high-resolution STS, EST, and gene-based physical map of the hereditary paraganglioma region on chromosome 11q23.

The genes responsible for hereditary paragangliomas (glomus tumors, MIM No. 168000) have been mapped to two distinct loci on the long arm of chromosome 11. Most of the informative families appear to be linked to the distal locus on chromosome 11q23 (PGL1), which has been previously confined to a 2-cM interval by haplotype analysis in an extended Dutch pedigree. To facilitate the identification of the PGL1 disease gene, we constructed an approximately 4-Mb ordered clone contig map of Sequence tagged sites, expressed sequence tags (ESTs), and known genes that spans the PGL1 critical region on chromosome 11q23. Among 29 new positional candidate ESTs, only two (EST100999 and EST241777) mapped within the PGL1 critical region. We further characterized the genomic organization of the promyelocytic leukemia zinc finger (PLZF) gene that maps within the PGL1 critical region and physically excluded the serotonin receptor type 3 (5HT3R) gene. Finally, we identified a common, silent, single-base substitution polymorphism in the 5HT3R gene and characterized the allele sets of two new highly polymorphic microsatellite repeats within the PGL1 critical region.

Alleles↗
PubMed1997

11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis.

Deletions of the long arm of chromosome 11 (11q) are one of the most frequent structural chromosome aberrations in various types of lymphoproliferative disorders. However, in most conventional chromosome banding studies of B-cell chronic lymphocytic leukemia (B-CLL), 11q deletions were not identified as a frequent aberration. The objective of this study was to analyze the frequency and clinical impact of 11q deletions in B-CLL by interphase cytogenetics using fluorescence in situ hybridization (FISH). Mononuclear cells from 214 patients with B-CLL were studied by FISH using the yeast artificial chromosome (YAC) clone 755b11 from chromosome region 11q22.3-q23.1; we previously showed that this clone was contained within a 2- to 3-Mb sized segment of 11q commonly deleted in lymphoproliferative disorders. Forty-three of the 214 (20%) tumors exhibited 11q deletions; 11q deletions were the second most frequent chromosome aberration following 13q14 (RB1 and/or D13S25) deletions (45%); they were more frequent than trisomy 12 (15%) or deletion of 17p (TP53 gene) (10%). Patients with 11q deletions were younger (P = .01) and had more advanced clinical stages (P = .01). 11q deletions were associated with extensive peripheral, abdominal, and mediastinal lymphadenopathy (P < .001). Patients with 11q deletions had a more rapid disease progression as shown by a shorter treatment-free interval (9 months v 43 months; P < .001). The prognostic effect of 11q deletion on survival strongly depended on the age: in patients less than 55 years old, the median survival time was significantly shorter in the deletion group (64 months v 209 months; P < .001), whereas in patients > or = 55 years old there was no significant difference (94 months v 111 months; P = .82). 11q deletions identify a new clinical subset of B-CLL characterized by extensive lymph node involvement. In younger B-CLL patients, this aberration is an important predictor of survival.

Adult↗
PubMed1997

Partial structure, chromosome localization, and expression of the mouse Icln gene.

The molecular identities of most volume-regulated ion channel proteins and putative regulatory elements are currently unknown. Recently, a role for a nucleotide-sensitive chloride conductance regulator, ICln, in the function of a ubiquitous volume-regulated chloride channel has been suggested. Here, we report the cloning of a fragment of the mouse Icln gene and identification of probable Icln pseudogenes. The functional Icln gene was mapped independently to human chromosome 11q13.5-q14 and mouse chromosome 7 (50.3 cM). ICln mRNA was shown to be abundantly expressed and evenly distributed in all mouse tissues examined and at four stages of embryonic development, consistent with the proposed role of ICln in the regulation of a ubiquitous chloride channel.

Amino Acid Sequence↗
PubMed1997

Why map the rat?

Explore the source record for details and available documents.

Animals↗
PubMed1997

Biallelic mutations in the ATM gene in T-prolymphocytic leukemia.

Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, genome instability and predisposition to malignancies, particularly T-cell neoplasms. The responsible gene, designated ataxia-telangiectasia mutated (ATM), was recently identified by positional cloning in the chromosomal region 11q22.3-23.1 (ref. 4, 5) ATM is 150 kb in length, consists of 66 exons and encodes a nuclear phosphoprotein of approximately 350 kDa (ref. 4-9). Although ATM is considered to be a tumorigenic factor in several human cancers, it has not yet been found mutated in tumors of non-AT patients. Given the marked predisposition of AT patients to develop neoplasms of the T-cell lineage, we analyzed a series of T-cell leukemias (T-prolymphocytic leukemia, or T-PLL) in non-AT patients in search of genomic changes associated with the development of this disease. Among the recurrent aberrations identified, deletion of the chromosome arm 11q was very frequent. Subsequent molecular cytogenetic analyses allowed us to define a small commonly deleted segment at 11q22.3-23.1 in 15 of 24 T-PLLs studied. Since this critical region contained ATM, we further analyzed the remaining copy of the gene in six cases showing deletions affecting one ATM allele. In all six cases, mutations of the second ATM allele were identified, leading to the absence, premature truncation or alteration of the ATM gene product. Thus, our study demonstrates disruption of both ATM alleles by deletion or point mutation in T-PLL, suggesting that ATM functions as a tumor-suppressor gene in tumors of non-AT individuals.

Alleles↗
PubMed1997

Location of the first genetic locus, PKDr1, controlling autosomal dominant polycystic kidney disease in Han:SPRD cy/+ rat.

The Han:SPRD cy/+ strain develops a form of slowly progressive disease that appears similar in many respects to that seen in the autosomal dominant polycystic kidney disease (ADPKD) in humans. We have performed a total genome scan in an experimental backcross population derived from affected Han:SPRD cy/+ rat (PKD) and non-affected Wistar Ottawa Karlsburg rat (WOK) using 117 microsatellite markers. The genetic dissection of PKD allowed us to map on rat chromosome 5, a quantitative trait locus (QTL) controlling PKD, kidney mass and plasma urea concentration. The homology region is likely to reside on human chromosome 8. The gene responsible for PKD in Han:SPRD cy/+ rat is neither PKD1, localised on human chromosome 16, nor PKD2, localised on human chromosome 4. Therefore, we propose that this new locus be denoted PKDr1. The detection of the PKDr1 locus and associated QTL should accelerate research into the genetic causes of ADPKD.

Animals↗
PubMed1997

A linkage map of the rat genome derived from three F2 crosses.

We report the construction of a dense linkage map of the rat genome integrating 767 simple sequence length polymorphism markers, combined over three crosses with high rates of polymorphism. F2 populations from WKY x S (n = 159), BN x S (n = 91), and BN x GK (n = 139) were selected and genotyped for combinations of microsatellite markers. The loci define 21 linkage groups corresponding to the 20 rat autosomal chromosomes and the X chromosome. The map spans a genetic length of 1998 cM. This combined linkage map should facilitate the advancement of genetic studies for a wide variety of rat models characterized for complex phenotypes.

Animals↗
PubMed1997

Fine mapping of an imprinted gene for familial nonchromaffin paragangliomas, on chromosome 11q23.

Hereditary nonchromaffin paragangliomas (PGL; glomus tumors; MIM 168000) are mostly benign, slow-growing tumors of the head and neck region, inherited from carrier fathers in an autosomal dominant fashion subject to genomic imprinting. Genetic linkage analysis in two large, unrelated Dutch families assigned PGL loci to two regions of chromosome 11, at 11q23 (PGL1) and 11q13.1 (PGL2). We ascertained a total of 11 North American PGL families and confirmed maternal imprinting (inactivation). In three of six families, linkage analysis provided evidence of linkage to the PGL1 locus at 11q23. Recombinants narrowed the critical region to an approximately 4.5-Mb interval flanked by markers D11S1647 and D11S622. Partial allelic loss of strictly maternal origin was detected in 5 of 19 tumors. The greatest degree of imbalance was detected at 11q23, distal to D11S1327 and proximal to CD3D. Age at onset of symptoms was significantly different between fathers and children (Wilcoxon rank-sum test, P < .002). Affected children had an earlier age at onset of symptoms in 39 of 57 father-child pairs (chi2 = 7.74, P < .006). However, a more conservative comparison of the number of pairs in which a child had > or = 5 years earlier age at onset (n = 33) vis-a-vis that of complementary pairs (n = 24) revealed no significant difference (chi2 = 1.42, P > .2). Whether these data represent genetic anticipation or ascertainment bias can be addressed only by analysis of a larger number of father-child pairs.

Adolescent↗
PubMed1996

A gene map of the human genome.

The human genome is thought to harbor 50,000 to 100,000 genes, of which about half have been sampled to date in the form of expressed sequence tags. An international consortium was organized to develop and map gene-based sequence tagged site markers on a set of two radiation hybrid panels and a yeast artificial chromosome library. More than 16,000 human genes have been mapped relative to a framework map that contains about 1000 polymorphic genetic markers. The gene map unifies the existing genetic and physical maps with the nucleotide and protein sequence databases in a fashion that should speed the discovery of genes underlying inherited human disease. The integrated resource is available through a site on the World Wide Web at http://www.ncbi.nlm.nih.gov/SCIENCE96/.

Amino Acid Sequence↗
PubMed1996

Molecular cytogenetic delineation of a novel critical genomic region in chromosome bands 11q22.3-923.1 in lymphoproliferative disorders.

Aberrations of the long arm of chromosome 11 are among the most common chromosome abnormalities in lymphoproliferative disorders (LPD). Translocations involving BCL1 at 11q13 are strongly associated with mantle cell lymphoma. other nonrandom aberrations, especially deletions and, less frequently, translocations, involving bands 11q21-923 have been identified by chromosome banding analysis. To date, the critical genomic segment and candidate genes involved in these deletions have not been identified. In the present study, we have analyzed tumors from 43 patients with LPD (B-cell chronic lymphocytic leukemia, n = 40; mantle cell lymphoma, n = 3) showing aberrations of bands 11q21-923 by fluorescence in situ hybridization. As probes we used Alu-PCR products from 17 yeast artificial chromosome clones spanning chromosome bands 11q14.3-923.3, including a panel of yeast artificial chromosome clones recognizing a contiguous genomic DNA fragment of approximately 9-10 Mb in bands 11q22.3-923.3. In the 41 tumors exhibiting deletions, we identified a commonly deleted segment in band 11q22.3-923.1; this region is approximately 2-3 Mb in size and contains the genes coding for ATM (ataxia telangiectasia mutated), RDX (radixin), and FDX1 (ferredoxin 1). Furthermore, two translocation break-points were localized to a 1.8-Mb genomic fragment contained within the commonly deleted segment. Thus, we have identified a single critical region of 2-3 Mb in size in which 11q14-923 aberrations in LPD cluster. This provides the basis for the identification of the gene(s) at 11q22.3-923.1 that are involved in the pathogenesis of LPD.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1996

Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat.

Goto-Kakizaki (GK) rats are a well characterized model for non-insulin dependent diabetes mellitus (NIDDM). We have used a combination of physiological and genetic studies to identify quantitative trait loci (QTLs) responsible for the control of glucose homeostasis and insulin secretion in a F2 cohort bred from spontaneously diabetic GK rats. The genetic dissection of NIDDM allowed us to map up to six independently segregating loci predisposing to hyperglycaemia, glucose intolerance or altered insulin secretion, and a seventh locus implicated in body weight. QTLs implicated in glucose tolerance and adiposity map to the same region of rat chromosome 1, and may indicate the influence of a single locus. Our study demonstrates that distinct combinations of genetic loci are responsible for different physiological characteristics associated with the diabetic phenotype in the GK rat, and it constitutes an important step for directing the search for the genetic factors involved in human NIDDM.

Animals↗
PubMed1996

A major quantitative trait locus influences hyperactivity in the WKHA rat.

The syndrome of hyperactivity describes behavioural disorders existing mainly in children and characterized by increased levels of motor activity, inattention and impulsivity. Overall the aetiology is poorly understood due to the heterogeneity of the pathology although psychological, biological and social factors acting singly or in concert are generally thought to be involved. In animal studies the observed hyperactivity phenotype results from relative participation of exploration, emotionality and general activity. Studies using brain lesions, neuropharmacology and gene knock-out strategies have shown that specific elements of the brain dopaminergic system can subserve hyperactivity. Evidence of a genetic contribution comes from family and twin studies but also from the ability to select divergent animal lines on the basis of their differential activity. The Wistar-Kyoto (WKY) and Wistar-Kyoto hyperactive (WKHA) rats are such strains--distinct for their low and high activity scores in a novel environment, respectively. Here, we report the detection of a major hyperactivity-related QTL on chromosome 8, explaining 29% of the variance of an intercross between these strains. This study represents the first behavioural QTL analysis in rat and provides a new starting point for biologically categorizing different forms of hyper-activity.

Animals↗
PubMed1996

A high resolution CEPH crossover mapping panel and integrated map of chromosome 11.

High resolution (0.1 cM) CEPH crossover mapping panels were constructed for chromosome 11. These panels will facilitate a transition from top-down physical and genetic mapping strategies to integrated breakpoint mapping strategies. Novel methods, which differ from other methods in overcoming the limitations of incomplete heterozygosity and variable marker density, were developed for creating the panels and integrated maps. This made it possible to identify and sublocalize the majority of crossovers in 61 families. The panels were used to map 139 microsatellite markers. A semi-integrated map and a fully-integrated map were constructed by combining these data with data from CEPH 7.1 and then integrating data from the radiation hybrid (RH) map. Genetic lengths estimated from the mapping panels were similar to the estimates obtained when all recombinant and non-recombinant offspring were included (189.4 cM in females and 126.1 cM in males), indicating that genetic distances are stable at this high marker density. The maps have a cM density of 0.62. The distance between ordered markers is 1.39-2.92 cM depending on the criterion for order and the extent of map integration. The 2D maps provide the resolution and flexibility needed to enhance current applications such as positional cloning and mapping complex disorders; while the mapping panels will greatly improve the resolution, reliability and efficiency of future genetic mapping.

Chromosome Mapping↗
PubMed1996

Cerebral oximetry and stroke distance: the future of emergency department monitoring?

OBJECTIVE: To illustrate the possible role of cerebral oximetry and stroke distance as measured by Doppler ultrasound in monitoring the critically ill patient non-invasively in the emergency department. METHODS: Five critically ill patients were monitored with either cerebral oximetry or both cerebral oximetry and stroke distance (the distance travelled by blood in the aorta with each ventricular contraction), as measured by Doppler ultrasound of the aortic arch. CONCLUSIONS: Stroke distance as measured by Doppler ultrasound was a good clinical indication of reduced stroke volume and hence of cardiac output. Cerebral oximetry appears to be a useful measure of tissue hypoxia in patients in whom pulse oximetry is either unrecordable or unreliable.

Adolescent↗