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D Malo

Publications and source records attributed to D Malo.

At least 55 records · Page 3Linked to original sources
PubMed1994

The mouse neurofibromatosis type 2 gene maps to chromosome 11.

Neurofibromatosis type 2 (NF2) is a dominantly inherited disease characterized by the development of bilateral vestibular schwannomas and meningiomas, which together represent 30% of primary brain tumors. The NF2 gene, which has recently been isolated, maps to the long arm of human chromosome 22. Using recombinant inbred mice, we have determined the chromosomal position of the mouse homologue of the NF2 gene. Analysis of the allele distribution in AKXD recombinant inbred strains using a simple sequence repeat polymorphism (D11Mcg1) in the 3' untranslated region of the mouse cDNA maps the mouse NF2 gene to the proximal region of chromosome 11, closely linked to Pmv-2. This region also contains the genes for leukemia inhibitory factor and neurofilament heavy-chain polypeptide and thus represents a region of conserved synteny between human chromosome 22 and mouse chromosome 11. Using additional polymorphic markers, we established the following locus order from the centromere: D11Mit1/D11Mit72/D11Mcg1-D11Mit74-Pmv-2-D11Mi t2-D11Mit77/D11Mit78/D11Mit63.

Alleles↗
PubMed1994

Characterization of a region-specific library of microclones in the vicinity of the Bcg and splotch loci on mouse chromosome 1.

The proximal portion of mouse chromosome 1 harbors a variety of mutant loci that have yet to be characterized at the molecular level. We have constructed a library of genomic DNA fragments from the proximal portion of mouse chromosome 1 by microdissection and microcloning techniques, with the aim of generating genetic markers in close proximity to some of these mutant loci. To facilitate the genetic mapping of 27 microclones from this library, we divided a 56-cM segment of chromosome 1 between the Col3a1 and Ren 1,2 genes into eight intervals defined by anchor loci. Restriction fragment length polymorphisms were determined for each of the microclones and their segregation with the anchor loci was followed in informative animals from a panel of 252 interspecific backcross mice (C57BL/6J x Mus spretus) x C57BL/6J. We were able to assign 26 of 27 (96%) randomly selected microclones to each of the defined chromosome 1 intervals. A total of eight microclones mapped within the large interstitial deletion found in the Spr mouse mutant. Two of these clones were found to be tightly linked to the host resistance locus Bcg and at least one was found to be linked to the neural tube defect mutant splotch. Other clones mapped to intervals containing several other mouse mutants. These novel DNA markers should aid in positional cloning strategies presently employed to identify these mutant loci. These clones should also be useful in the creation of both physical and YAC contiguous maps of the proximal portion of mouse chromosome 1.

Animals↗
PubMed1994

Genetic control of host resistance to infection.

Human resistance to infectious diseases is often regulated by multiple genes that control different aspects of host-parasite interaction. Genetically distinct inbred strains of mice that differ in their susceptibility to specific pathogens are invaluable for dissecting such complex patterns and have allowed the identification of several host-resistance loci that regulate natural and acquired immunity in response to infection. Cloning these genes is the first step in elucidating their roles in host defense.

Animals↗
PubMed1994

Genes of stress in experimental hypertension.

1. A significant portion of blood pressure variance is modified by the environment. 2. The present report summarizes evidence that: (i) the environmental response is genetically determined; (ii) various stressors can evoke a differential response in hypertensive animals and constitute its intermediate phenotypes; (iii) the response to heat stress can be assigned to a single 'thermosensitivity' locus; (iv) candidate genes of susceptibility to environmental stresses are member(s) of the heat stress gene (HSP) gene families; (v) a restriction fragment length polymorphism of hsp70 and a single base mutation in the 3'-untranslated region of hsp27 are associated with hypertension in recombinant inbred strains. 3. In conclusion, HSP gene variants may be causative in susceptibility to hypertension.

Animals↗
PubMed1993

Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg.

Natural resistance to infection with intracellular parasites is controlled by a dominant gene on mouse chromosome 1, called Bcg, Lsh, or Ity. Bcg affects the capacity of macrophages to destroy ingested intracellular parasites early during infection. We have assembled a 400 kb bacteriophage and cosmid contig within the genomic interval containing Bcg. A search for transcription units by exon amplification identified six novel genes in this contig. RNA expression studies showed that one of them, designated Nramp, was expressed exclusively in macrophage populations from reticuloendothelial organs and in the macrophage line J774A. Nramp encodes an integral membrane protein that has structural homology with known prokaryotic and eukaryotic transport systems, suggesting a macrophage-specific membrane transport function. Susceptibility to infection (Bcgs) in 13 Bcgr and Bcgs strains tested is associated with a nonconservative Gly-105 to Asp-105 substitution within predicted transmembrane domain 2 of Nramp.

Amino Acid Sequence↗
PubMed1993

High-resolution linkage map in the vicinity of the host resistance locus Bcg.

The mouse chromosome 1 locus Bcg determines natural resistance/susceptibility of inbred mouse strains to infection with antigenically unrelated intracellular parasites, including several Mycobacterium species, Salmonella typhimurium, and Leishmania donovani. In our effort to clone Bcg, we have constructed a high-resolution genetic linkage map in the vicinity of the gene. We have developed eight new highly polymorphic markers (simple sequence repeats) corresponding to cloned genes (Vil, Inha, Des), microdissected chromosome 1 anonymous probes (lambda Mm1C136, lambda Mm1C163, lambda Mm1C165), or novel DNA markers from the region obtained by chromosome walking (D1Mcg101 and D1Mcg105). We have followed the cosegregation of these markers with respect to Bcg in a novel panel of 1000 (C57L/J x C57BL/6J) x C57BL/6J segregating backcross mice. Additional segregation analyses were carried out in preexisting panels of intra- and interspecific backcross mice and recombinant inbred strains. Three of these markers were found to be very tightly linked to Bcg: lambda Mm1C165 did not show recombination with Bcg in 1424 meioses analyzed, while D1Mcg105 and lambda Mm1C136 were located 0.1 cM proximal and 0.2 cM distal to Bcg, respectively. This analysis enabled us to define further the proximal and distal boundaries of the Bcg interval: the proximal limit was defined by a single crossover occurring between D1Mcg105 and Bcg/lambda Mm1C165/Vil, and the distal limit by 1 cross-over between Bcg/lambda Mm1C165/Vil and lambda Mm1C136 in 1683 and 575 informative meioses, respectively, for a maximal interval of 0.3 cM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Physical delineation of the minimal chromosomal segment encompassing the murine host resistance locus Bcg.

The host resistance locus Bcg determines resistance of mice to infection with intracellular pathogens such as certain species of Mycobacteria, Salmonella typhimurium, and Leishmania donovani. Bcg maps on the proximal portion of mouse chromosome 1, very tightly linked to villin (Vil), with the gene order and intergene distances Tp-1-(1 cM)-D1Mcg105-(0.1 cM)-lambda Mm1C165/Vil/Bcg-(0.2 cM)-lambda Mm1C136-(0.3 cM)-Des-(0.1 cM)-Inha. In an effort to clone genomic sequences overlapping Bcg, we have used pulsed-field gel electrophoresis (PFGE) and fluorescence in situ hybridization to construct a physical map of the 3.9-Mb segment of proximal mouse chromosome 1, near Bcg. In situ hybridization to metaphase mouse chromosomes indicates that the mapped region is within band C5. Physical mapping of the Tp-1-Vil and lambda Mm1C136-Inha intervals was carried out by PFGE analysis, whereas the Vil-Des interval was estimated by in situ hybridization to interphase nuclei. Results of these combined analyses indicate the following locus order and maximal interlocus distances: Tp-1-(1000 kb)-D1Mcg105-(160 kb)-lambda Mm1C165-(180 kb)-Vil-(800 kb)-lambda Mm1C136-(290 kb)-Des-(130 kb)-Inha. Detailed restriction mapping of this region identifies numerous putative CpG islands, suggesting that several transcription units are present in the vicinity of Bcg.

Animals↗
PubMed1993

Genes encoding the H,K-ATPase alpha and Na,K-ATPase alpha 3 subunits are linked on mouse chromosome 7 and human chromosome 19.

We have used linkage analysis and fluorescence in situ hybridization to determine the chromosomal organization and location of the mouse (Atp4a) and human (ATP4A) genes encoding the H,K-ATPase alpha subunit. Linkage analysis in recombinant inbred (BXD) strains of mice localized Atp4a to mouse Chromosome (Chr) 7. Segregation of restriction fragment length polymorphisms in backcross progeny of Mus musculus x Mus spretus mating confirmed this assignment and indicates that Atp4a and Atp1a3 (gene encoding the murine Na,K-ATPase alpha 3 subunit) are linked and separated by a distance of approximately 2 cM. Analysis of the segregation of simple sequence repeats suggested the gene order centromere-D7Mit21-D7Mit57/Atp1a3-D7Mit72/Atp 4a. A human Chr 19-enriched cosmid library was screened with both H,K-ATPase alpha and Na,K-ATPase alpha 3 subunit cDNA probes to isolate the corresponding human genes (ATP4A and ATP1A3, respectively). Fluorescence in situ hybridization with gene-specific cosmid clones localized ATP4A to the q13.1 region, and proximal to ATP1A3, which maps to the q13.2 region, of Chr 19. These results indicate that ATP4A and ATP1A3 are linked in both the mouse and human genomes.

Animals↗
PubMed1992

Identification and mapping of six microdissected genomic DNA probes to the proximal region of mouse chromosome 1.

Six independent DNA probes, lambda Mm1C-150, lambda Mm1C-153, lambda Mm1C-156, lambda Mm1C-162, lambda Mm1C-163, and lambda Mm1C-165, have been isolated from a library of microdissected fragments from mouse chromosome 1, spanning cytogenetic bands C2 to C5. These DNA probes have been mapped by restriction fragment length polymorphism analysis with respect to 12 marker loci previously assigned to this portion of mouse chromosome 1, in a panel of 251 segregating Mus spretus x C57BL/6J interspecific backcross mice. The gene order and intergene distances were determined by segregation analysis to be centromere- lambda Mm1C-162-11.1 cM-Col3a1-8.8 cM-Len-2-2.6 cM-lambda Mm1C-163-1.6 cM-Fn-1-1.6 cM-Tp-1-0.8 cM-lambda Mm1C-165/Vil-0.4 cM-Inha-2.8 cM-lambda Mm1C-153-2.4 cM-lambda Mm1C-156-1.2 cM-Pax-3-5.6 cM-Akp-3-0.8 cM-Acrg-2.0 cM-Sag-0.5 cM-Col6a3-1.8 cM-lambda Mm1C-150-15.4 cM-Ren1,2. Four of these probes map within a chromosome 1 segment that is homologous to human chromosome 2q. Southern blotting analyses indicate that one of these anonymous probes, lambda Mm1C-165, detects DNA fragments highly conserved across species. These novel polymorphic probes should prove useful for linkage and physical mapping of this chromosomal region.

Animals↗
PubMed1992

Isolation of a yeast gene encoding a protein homologous to the human Tat-binding protein TBP-1.

We have cloned a putative yeast homolog of the gene encoding the human Tat-binding protein, TBP-1. The gene termed TBPY encodes a 45,243-dalton protein displaying a heptad repeat of hydrophobic amino acids reminiscent of a leucine zipper. Secondary structure predictions suggest the possibility of formation of an amphipathic helix that could further be organized into a coiled-coil. Additionally, the protein product of TBPY shows amino acid signatures characteristic of a large family of RNA and DNA helicases. We propose that the hydrophobic region of yTBP-1 participates in self-dimerization or heterodimerization.

ATPases Associated with Diverse Cellular Activitie↗
PubMed1991

The host resistance locus Bcg is tightly linked to a group of cytoskeleton-associated protein genes that include villin and desmin.

In the mouse, innate resistance or susceptibility to infection with a group of unrelated intracellular parasites which includes, Mycobacteria, Salmonella, and Leishmania is determined by the expression of a single dominant autosomal gene designated Bcg located on the proximal portion of chromosome 1. The gene is expressed at the level of the mature tissue macrophage and influences its capacity to restrict intracellular proliferation of the parasites. We have used restriction fragment length polymorphism analysis in segregating populations of inter- and intraspecific backcross mice and in recombinant inbred strains to position four new marker genes, transition protein 1 (Tp-1), desmin (Des), the alpha subunit of inhibin (Inha), and retinal S-antigen (Sag), in the vicinity of the host resistance locus, Bcg. The gene order for Tp-1, Des, Inha, and Sag was established in an eight-point testcross with respect to anchor loci previously assigned to that portion of mouse chromosome 1 and was found to be centromere-Fn-1-Tp-1-(Vil,Bcg)-Des-Inha-Akp-3-Acrg+ ++-Sag. Two of these new marker genes were found very tightly linked to Bcg: Des was located 0.3 +/- 0.3 cM distal from (Vil,Bcg) and 0.3 +/- 0.3 cM proximal to Inha. Tp-1 mapped 0.8 +/- 0.8 cM proximal and Sag 12.8 +/- 1.7 cM distal to (Vil,Bcg). Tp-1, Des, Inha, and Sag all fall within a large mouse chromosome 1 segment homologous with the telomeric region of the long arm of human chromosome 2 (2q). Our findings indicate that the two closest markers to the host resistance locus, Bcg, encode cytoskeleton-associated proteins which are capable of interaction with actin filaments.

Animals↗
PubMed1991

Three brain sodium channel alpha-subunit genes are clustered on the proximal segment of mouse chromosome 2.

We have used long-range physical mapping and restriction fragment length polymorphisms between two mouse species to determine the chromosomal organization and location of the genes encoding three distinct isoforms of the alpha-subunit of the brain sodium channel. Physical mapping by pulsed-field gel electrophoresis has established that Scn2a and Scn3a (genes encoding type II and type III sodium channel alpha-subunit isoforms) are physically linked and are separated by a maximum distance of 600 kb. The segregation of restriction fragment length variations in backcross progeny of a Mus musculus and Mus spretus mating indicates that Scn 1 a (gene encoding the type I sodium channel alpha subunit) and Scn2a are tightly linked and are separated by a distance of 0.7 cM. Linkage analysis in backcross and recombinant inbred (BXD and AKXD) strains of mice localized the three sodium channel genes to the proximal segment of mouse chromosome 2 and suggested the probable gene order centromere-Hc-Neb-Pmv7-Scn2a/Scn3a-Scn1a-Mpmv 14. These results indicate that the three isoforms of the brain sodium channel alpha-subunit are encoded by three distinct genes that share a common ancestral origin.

Abnormalities, Multiple↗
PubMed1991

Molecular characterization of a deletion encompassing the splotch mutation on mouse chromosome 1.

We have used a set of markers newly assigned to the proximal portion of mouse chromosome 1 to characterize the chromosomal segment deleted in the splotch-retarded (Spr) mouse mutant. Among nine markers tested in the heterozygote Spr/+mouse, we have identified four genes, Vil, Des, Inha, and Akp-3, which map within the Spr deletion. The closest distal marker to the deletion is the Acrg gene, with the distal deletion breakpoint mapping within the 0.8-cM segment separating Akp-3 and Acrg. The most proximal gene to the Spr deletion is Tp1. The proximal deletion breakpoint maps within the 0.8-cM segment separating Tp1 and Vil. The minimum size of the Spr deletion would therefore be limited to 14 cM, the genetic distance between Vil and Akp-3. The maximum size of the Spr deletion is estimated to be 16 cM, the genetic distance between Tp1 and Acrg.

Animals↗
PubMed1991

Genetic control of innate resistance to mycobacterial infections.

The Mendelian segregation of resistance to infection in different strains of mice infected with mycobacteria, Salmonella and Leishmania spp, all of which live in macrophages, is currently under close scrutiny. Here, Erwin Schurr and colleagues review the nature and function of the Bcg gene in controlling innate resistance to mycobacterial infection in mice and speculate on the occurrence of a possible human equivalent.

Animals↗
PubMed1991

Molecular genetics of inherited susceptibility to intracellular parasites.

In the mouse, innate susceptibility to infection with mycobacteria is controlled by the Bcg host resistance locus. Phenotypically, the locus displays two alleles, a dominant resistance and a recessive susceptibility allele. The cell type expressing the resistance locus is the mature tissue macrophage. We have immortalized macrophages from Bcgr and Bcgs mice and found that macrophage cell lines of Bcgr origin, in comparison to those derived from Bcgs mice have an increased microbicidal activity and show increased expression of a number of molecules known to be associated with macrophage activation. This is in agreement with our earlier finding that Bcgr macrophages are at an advanced stage of macrophage priming for activation. The Bcg gene is located on the proximal region of mouse Chromosome 1. We have obtained a detailed genetic map in the vicinity of Bcg and identified three markers within 1 cM of the resistance locus. These three markers have been used for the generation of a physical map of this area of mouse Chromosome 1 and can be used as anchor points for the cloning of the Bcg host resistance gene. The chromosomal segment in the proximity of the Bcg locus in the mouse is precisely conserved on the telomeric region of the long arm of human Chromosome 2. Investigations of linkage of genetic markers present on human Chromosome 2q with susceptibility to tuberculosis have so far generated a LOD score of + 2.4. Linkage of Chromosome 2q markers with susceptibility to mycobacterial disease supports the existence of susceptibility genes in humans and suggests a human homologue of the mouse Bcg gene as a prime candidate for a human innate susceptibility locus.

Animals↗