Biomedical subjects

C Julier

Publications and source records attributed to C Julier.

At least 19 recordsLinked to original sources

PubMed1992

Maternal inheritance of atopic IgE responsiveness on chromosome 11q.

Atopy is a common familial state underlying allergic asthma and rhinitis. Lately, we have assigned a gene for atopy to chromosome 11q by linkage to the marker D11S97. Since previous studies have suggested that the risk of atopy is higher for children of atopic mothers than for those of atopic fathers, we sought differences between maternal and paternal patterns of transmission at the 11q13 locus among pairs of siblings in families affected by atopy. When we defined atopy as the presence of a positive skinprick test (greater than or equal to 2 mm) to any of a panel of common allergens, a higher than normal concentration of total serum IgE, or a positive radioallergosorbent test for a specific IgE, we found that 125 (62%) of the sibling-pairs affected by atopy shared the maternal 11q13 allele and 78 (38%) did not. This distribution differs significantly from the expected 50/50 distribution (p = 0.001). Of paternally derived alleles, 83 (46%) were shared and 96 (54%) were not (not significantly different from 50/50). The result was similar whatever definition of atopy was used and with other genetic markers on 11q. These findings show that transmission of atopy at the chromosome 11q locus is detectable only through the maternal line. The pattern of inheritance is consistent either with paternal genomic imprinting or with maternal modification of developing immune responses.

Alleles↗

PubMed1992

Linkage analysis in juvenile neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinosis (NCL, Batten disease) is an autosomal recessive disease characterized by progressive mental retardation, cortical atrophy, seizures, and retinal degeneration. Several subtypes have been delineated on the basis of age-at-onset and histological characteristics; the most common is the juvenile (JNCL) form. Recently, the gene for JNCL was shown to reside on chromosome 16 through linkage studies to the haptoglobin locus and anonymous DNA markers using numerous European families. We have now examined 8 families from North America with JNCL for linkage to markers in 16q21-23. Results in 3 families tend to support linkage to chromosome 16;3 families remained uninformative, and 2 families produced negative lod scores in this region. A test of homogeneity was suggestive, but could not significantly reject the null hypothesis of homogeneity. We are continuing to collect families, particularly those with multiple living affecteds, and are identifying other probes in this region. Given close localization on chromosome 16 for JNCL, molecular strategies, including candidate gene strategies, are being explored.

Child↗

PubMed1992

Ataxia-telangiectasia: linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome.

Ataxia-telangiectasia (A-T) is a progressive autosomal recessive disease featuring neurodegeneration, immunodeficiency, chromosomal instability, radiation sensitivity and a highly increased proneness to cancer. A-T is ethnically widespread and genetically heterogeneous, as indicated by the existence of four complementation groups in this disease. Several "A-T-like" genetic diseases share various clinical and cellular characteristics with A-T. By using linkage analysis to study North American and Turkish A-T families, the ATA (A-T, complementation group A) gene has been mapped to chromosome 11q23. A number of Israeli Arab A-T patients coming from large, highly inbred families were assigned to group A. In one of these families, an additional autosomal recessive disease was identified, characterized by ataxia, hypotonia, microcephaly and bilateral congenital cataracts. In two patients with this syndrome, normal levels of serum immunoglobulins and alpha-fetoprotein, chromosomal stability in peripheral blood lymphocytes and skin fibroblasts, and normal cellular response to treatments with X-rays and the radiomimetic drug neocarzinostatin indicated that this disease does not share, with A-T, any additional features other than ataxia. These tests also showed that another patient in this family, who is also mentally retarded, is affected with both disorders. This conclusion was further supported by linkage analysis with 11q23 markers. Lod scores between A-T and these markers, cumulated over three large Arab families, were significant and confirmed the localization of the ATA gene to 11q23. However, another Druze family unassigned to a specific complementation group, showed several recombinants between A-T and the same markers, leaving the localization of the A-T gene in this family open.

Ataxia↗

PubMed1992

Identification of a CA repeat at the TCRA locus using yeast artificial chromosomes: a general method for generating highly polymorphic markers at chosen loci.

The creation of a comprehensive genetic map in human has been limited by the lack of highly polymorphic markers spaced evenly throughout the human genome. We have utilized yeast artificial chromosomes (YAC) containing large human DNA inserts to help identify highly polymorphic (CA)n repeats at a chosen locus. The DNA of a YAC containing the locus was subcloned in M13 vectors, and the recombinants were screened at high stringency to detect preferentially long (CA)n repeats (n greater than 20). These repeats, which are the most likely to be highly polymorphic, were then studied to confirm both the level of polymorphism and their precise genetic location. This strategy has permitted the identification of a new, highly polymorphic CA repeat (77% heterozygosity) at the T cell receptor alpha chain (TCRA) locus on chromosome 14q. It provides a powerful marker for assessing the role of this locus in the susceptibility to autoimmune and infectious diseases. This approach should permit the development of highly polymorphic markers at any targeted locus and rapidly improve the current human genetic map.

Base Sequence↗

PubMed1991

Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility.

A class of alleles at the VNTR (variable number of tandem repeat) locus in the 5' region of the insulin gene (INS) on chromosome 11p is associated with increased risk of insulin-dependent diabetes mellitus (IDDM), but family studies have failed to demonstrate linkage. INS is thought to contribute to IDDM susceptibility but this view has been difficult to reconcile with the lack of linkage evidence. We thus investigated polymorphisms of INS and neighbouring loci in random diabetics, IDDM multiplex families and controls. HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kilobase segment spanned by the 5' INS VNTR and the third intron of the gene for insulin-like growth factor II (IGF2). As INS is the major candidate gene from this region, diabetic and control sequence were compared to identify all INS polymorphisms that could contribute to disease susceptibility. In multiplex families the IDDM-associated alleles were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. Our results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility which is located in a 19-kilobase region of INS-IGF2. Our results also suggest new ways to map susceptibility loci in other common diseases.

Base Sequence↗

PubMed1991

Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats.

The spontaneously hypertensive rat and the stroke-prone spontaneously hypertensive rat are useful models for human hypertension. In these strains hypertension is a polygenic trait, in which both autosomal and sex-linked genes can influence blood pressure. Linkage studies in crosses between the stroke-prone spontaneously hypertensive rat and the normotensive control strain Wistar-Kyoto have led to the localization of two genes, BP/SP-1 and BP/SP-2, that contribute significantly to blood pressure variation in the F2 population. BP/SP-1 and BP/SP-2 were assigned to rat chromosomes 10 and X, respectively. Comparison of the human and rat genetic maps indicates that BP/SP-1 could reside on human chromosome 17q in a region that also contains the angiotensin I-converting enzyme gene (ACE). This encodes a key enzyme of the renin-angiotensin system, and is therefore a candidate gene in primary hypertension. A rat microsatellite marker of ACE was mapped to rat chromosome 10 within the region containing BP/SP-1.

Animals↗

PubMed1991

Human variable number of tandem repeat probes as a source of polymorphic markers in experimental animals.

Human VNTR (Variable Number of Tandem Repeat) markers are examined as a source of polymorphism for linkage studies in inbred strains of mice and rats. High frequencies of cross-hybridization are found under fingerprinting conditions that detect many distinct minisatellite loci in these species. Linkage studies suggest that minisatellite markers are widely distributed in the mouse genome, in contrast to humans where they are clustered, particularly in telomeric regions. Human VNTR probes can be used to screen in mouse genomic libraries to isolate mouse specific VNTR sequences. Some of these sequences reveal fingerprint patterns under stringent hybridization conditions.

Animals↗

PubMed1991

Linkage relationship between incontinentia pigmenti (IP2) and nine terminal X long arm markers.

Linkage data for familial incontinentia pigmenti (IP2) and nine X chromosomal markers are reported. Previously found linkage between IP2 and the DXS52 locus is confirmed with the maximum lod score of 6.19 at a recombination fraction of 0.03. Linkage is also established with loci DXS134, DXS15 and DXS33. Multipoint analysis allows us to localize the IP2 locus outside a block of seven linked markers of the Xq28 region.

Chromosome Mapping↗

PubMed1991

Localization of an ataxia-telangiectasia locus to a 3-cM interval on chromosome 11q23: linkage analysis of 111 families by an international consortium.

Linkage of at least two complementation groups of ataxia-telangiectasia (AT) to the chromosomal region 11q23 is now well established. We provide here an 18-point map of the surrounding genomic region, derived from linkage analysis of 40 CEPH families. On the basis of this map, 111 AT families from Turkey, Israel, England, Italy, and the United States were analyzed, localizing the AT gene(s) to an 8-cM sex-averaged interval between the markers STMY and D11S132/NCAM. A new Monte Carlo method for computing approximate location scores estimates this location as being at least 10(8) times more likely than the next most likely interval, with a support interval midway between STMY and D11S132 that is either 5.2 cM (sex-averaged and conservatively based on 3 lod scores from the maximum-location score) or 2.8 cM (male specific, based on a 2.72:1 interval-specific female-to-male distance ratio.

Ataxia Telangiectasia↗

PubMed1991

High-resolution linkage mapping for susceptibility genes in human polygenic disease: insulin-dependent diabetes mellitus and chromosome 11q.

Insulin-dependent diabetes mellitus (IDDM) has a complex pattern of genetic inheritance. In addition to genes mapping to the major histocompatibility complex (MHC), several lines of evidence point to the existence of other genetic susceptibility factors. Recent studies of the nonobese diabetic mouse (NOD) model of IDDM have suggested the presence, on mouse chromosome 9, of a susceptibility gene linked to the locus encoding the T-cell antigen, Thy-1. A region on human chromosome 11q is syntenic to this region on mouse chromosome 9. We have used a set of polymorphic DNA markers from chromosome 11q to investigate this region for linkage to a susceptibility gene in 81 multiplex diabetic pedigrees. The data were investigated by maximization of lod scores over genetic models and by multiple-locus affected-sib-pair analysis. We were able to exclude the presence of a susceptibility gene (location scores less than -2) throughout greater than 90% of the chromosome 11q homology region, under the assumption that the susceptibility factor would cause greater than 50% of affected sib pairs to share two alleles identical by descent. Theoretical estimates of the power to map susceptibility genes with a high-resolution map of linked markers in a candidate region were made, using HLA as a model locus. This result illustrates the feasibility that IDDM linkage studies using mapped sets of polymorphic DNA markers have, both for other areas of the genome in IDDM and for other polygenic diseases. The analytic approaches introduced here will be useful for affected-sib-pair studies of other complex phenotypes.

Chromosome Mapping↗

PubMed1990

In situ hybridization ascertains the presence of a translocation t(6;11) in an acute monocytic leukemia.

In situ hybridization was performed in a case of acute monoblastic leukemia (FAB type M5b) with a rearrangement of the long arm of chromosome 11. Cytogenetic analysis after R- and G-banding showed an apparent deletion of 11q with a breakpoint at 11q23, and a translocation t(6;11) was suspected in certain metaphases. In situ hybridization with a biotinylated cosmid probe hybridizing at 11q25 confirmed the translocation t(6;11)(q27;q23). Use of nonradioactive in situ hybridization techniques for more precise characterization of chromosomal rearrangements in malignant cells is emphasized.

Bone Marrow↗

PubMed1990

A detailed genetic map of the long arm of chromosome 11.

We describe 14 new restriction fragment length polymorphisms, corresponding to 13 loci on the long arm of chromosome 11. A detailed genetic map of chromosome 11q has been constructed from these and other loci (a total of 31 loci) typed in 59 reference families. The 23 most informative markers were selected to establish a map with a strongly supported order; regional localizations are provided for eight other markers. The loci span 88 cM in males and 148 cM in females and form a dense continuum on 11q. These ordered polymorphic markers will be of help in studying the genes responsible for several diseases that have been localized to this region, including genes responsible for multiple endocrine neoplasia type I (MEN1), ataxia telangiectasia (AT), tuberous sclerosis (TSC), and some forms of asthma and rhinitis.

Chromosome Mapping↗

PubMed1990

Batten disease (Spielmeyer-Vogt disease, juvenile onset neuronal ceroid-lipofuscinosis) gene (CLN3) maps to human chromosome 16.

The ceroid-lipofuscinoses are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in neurons and other cell types. The underlying biochemical defect is unknown. Batten disease (Spielmeyer-Vogt disease, juvenile onset neuronal ceroid-lipofuscinosis) displays autosomal recessive inheritance. Genetic linkage studies were undertaken to determine the chromosomal location of the Batten disease mutation (CLN3). Following identification of linkage to the haptoglobin locus, linkage analysis has been carried out in 42 families by using DNA markers for loci on the long arm of human chromosome 16. The maximal lod score between Batten disease and the locus D16S148 calculated for combined sexes is 6.05 at a recombination fraction theta = 0.00. Multilocus analysis using five loci indicated the most likely order to be HP-D16S151-D16S150-CLN3-D16S148-D16S147. The maximal location score for CLN3 was 48 (equivalent to a lod score of 10.4) in that interval within this fixed marker map.

Chromosome Mapping↗

PubMed1990

Mapping of a gene determining tuberous sclerosis to human chromosome 11q14-11q23.

Tuberous sclerosis (TSC) is a dominantly inherited disorder characterized by hamartomas and hamartias in one or more organs, most often in skin, brain, and kidneys. Analysis of the basic genetic defect in tuberous sclerosis would be greatly expedited by definitive determination of the chromosomal location of the TSC gene or genes. We have carried out genetic linkage studies in 15 TSC families, using 34 polymorphic markers including protein markers and DNA markers. Pairwise lod scores were calculated using LIPED, and multipoint analyses were carried out using MENDEL. In the pairwise linkage analysis, using a penetrance value of 90%, a significant positive lod score was obtained with MCT128.1 (D11S144), 11q22-11q23, Zmax 3.26 at theta = 0.08. The tyrosinase probe TYR (11q14-11q22) gave a maximum lod score of 2.88 at theta = 0. In the multipoint analyses the most likely order is (TYR,TSC)-MCT128.1-HHH172. Homogeneity analysis was carried out using the USERM9 subprogram of MENDEL, which conducts the admixture test of C. Smith (1963, Ann. Hum. Genet. 27: 175-182). This test provided no evidence for genetic heterogeneity (that is, non-11-linked families) in this data set.

Alleles↗

PubMed1990

A primary map of 24 loci on human chromosome 16.

A primary genetic map of chromosome 16 has been constructed by linkage analysis of 24 polymorphic loci, typed in 59 reference families. These loci form a continuous map that covers the whole chromosome and spans genetic distances of 187 cM in males and 226 cM in females. Most of the sex-specific recombination rate difference comes from a nontelomeric region that covers 10 cM in males and 74 cM in females. Both telomeric regions show the opposite trend, with a significant increase in the male recombination rate.

Chromosome Fragility↗

PubMed1990

Gene mapping.

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Chromosome Mapping↗

PubMed1990

Minisatellite linkage maps in the mouse by cross-hybridization with human probes containing tandem repeats.

Tests of 29 human variable number of tandem repeat probes in inbred mouse lines showed that 80% (23/29) cross-hybridize, and 48% (14/29) produce multiple band, minisatellite polymorphisms (fingerprint patterns). Mini-satellite-type polymorphisms detected by 11 probes were characterized in eight different strains; on average, 240 polymorphic differences were detected between pairs of strains. Reproducible fingerprint patterns permit the study of the segregation of the minisatellite polymorphisms in experimentally designed crosses. As an example, we constructed primary minisatellite genetic linkage maps containing 346 polymorphic bands, distributed in 101 groups of closely linked systems, from genotypes on a recombinant inbred panel (C57BL/6J X DBA/2J); 38 of the groups were assigned by linkage to 15 autosomal chromosomes. The minisatellite genetic maps of C57BL/6J and DBA/2J can be applied in other linkage studies involving these strains.

Animals↗

PubMed1990

Simultaneous localization of cosmids and chromosome R-banding by fluorescence microscopy: application to regional mapping of human chromosome 11.

A technique for nonradioactive in situ hybridization on human metaphase chromosomes has been developed to localize human cosmid clones. The simple procedure using two fluorescent dyes (fluorescein and propidium iodide) allows the simultaneous identification of chromosomal R-bands and hybridization signal in a single screening of the slides. This technique has been used for rapid correlation of the genetic and physical map of chromosome 11q13-qter in the region of genes responsible for ataxia-telangiectasia and tuberous sclerosis.

Cell Line↗