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C Julier

Publications and source records attributed to C Julier.

At least 37 records · Page 2Linked to original sources
PubMed1995

A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) affects about 5% of the world population. The disease presents a polygenic mode of inheritance, but mechanisms and genes involved in late-onset NIDDM are largely unknown. We report the association of a single heterozygous Gly to Ser missense mutation in the glucagon receptor gene with late-onset NIDDM. This mutation was highly associated with NIDDM in a pooled set of French and Sardinian patients (chi 2 = 14.4, P = 0.0001) and showed some evidence for linkage to diabetes in 18 sibships from 9 French pedigrees (chi 2 = 6.63, P < 0.01). Receptor binding studies using cultured cells expressing the Gly40Ser mutation demonstrate that this mutation results in a receptor which binds glucagon with a three-fold lower affinity compared to the wild type receptor.

DNA Primers↗
PubMed1995

Regulation of insulin gene expression by the IDDM associated, insulin locus haplotype.

A 4.1 kb genomic region, spanning the insulin (INS) gene, confers genetic susceptibility to Type 1 or insulin-dependent diabetes mellitus (IDDM). Ten polymorphisms within this region form two predominant, complementary haplotypes. We have been studying the effects of these polymorphisms on the levels of insulin mRNA. Cloned genomic DNA fragments representing these two separate haplotypes were transiently transfected into a rodent pancreatic beta cell line, HIT-T15. These studies revealed that insulin mRNA levels were consistently higher in the transfectants expressing the diabetic haplotype. Over-expression of insulin mRNA may provide the basic mechanism for the diabetic susceptibility encoded at the INS locus.

Animals↗
PubMed1995

Evaluation of the SA locus in human hypertension.

The SA gene is expressed at 10-fold greater levels in the kidney of the spontaneously hypertensive rat compared with the normotensive Wistar-Kyoto rat. The gene is linked to blood pressure levels in a number of crosses involving the spontaneously hypertensive rat and other strains of genetically hypertensive rats. To assess its role in human hypertension, a human SA cDNA was cloned from a liver library. The cDNA was 1513 bp in length and exhibited a high identity with the published rat SA cDNA sequence in the coding region. A microsatellite marker was developed from a yeast artificial chromosome clone containing SA and mapped by linkage to human chromosome 16p13.11-12.3. Polymerase chain reaction amplification of human genomic DNA revealed two introns located in the SA gene, one of which contains a frequent polymorphism due to a single nucleotide substitution (cytosine to thymidine at residue 79 of the intron). Association and linkage studies in a large sample of hypertensive patients, normotensive control subjects, and multiplex sibships with these markers and other microsatellites in close proximity to SA revealed no evidence favoring involvement of the gene in the disease in humans. The methodology used in this study can be applied to the evaluation of other novel candidate genes obtained from investigations of experimental models of hereditary hypertension.

Adult↗
PubMed1995

Autosomal dominant exudative vitreoretinopathy: linkage analysis and its clinical application.

Close linkage without recombination (Zmax = 7.383 at Theta = 0.00) was found between the locus for autosomal dominant exudative vitreoretinopathy (Criswick-Schepens) and the locus D11S388 in 11q14.3-q21. We report on the application of data from linkage studies in the diagnostic management of this disease. To determine the disease risk for two newborn children of two affected mothers more precisely, indirect genotype analysis was performed by typing their DNA for three DNA polymorphisms, the loci of which have been shown to be closely linked to the locus of autosomal dominant exudative vitreoretinopathy.

Adult↗
PubMed1995

Segregation and linkage analysis of serum angiotensin I-converting enzyme levels: evidence for two quantitative-trait loci.

Human serum angiotensin I-converting enzyme (ACE) levels vary substantially between individuals and are highly heritable. Segregation analysis in European families has shown that more than half of the total variability in ACE levels is influenced by quantitative-trait loci (QTL). One of these QTLs is located within or close to the ACE locus itself. Combined segregation/linkage analysis in a series of African Caribbean families from Jamaica shows that the ACE insertion-deletion polymorphism is in moderate linkage disequilibrium with an ACE-linked QTL. Linkage analysis with a highly informative polymorphism at the neighboring growth-hormone gene (GH) shows surprisingly little support for linkage (LOD score [Z] = 0.12). An extended analysis with a two-QTL model, where an ACE-linked QTL interacts additively with an unlinked QTL, significantly improves both the fit of the model (P = .002) and the support for linkage between the ACe-linked QTL interacts additively with an unlinked QTL, significantly improves both the fit of the model (P = .002) and the support for linkage between the ACe-linked QTL and GH polymorphism (Z = 5.0). We conclude that two QTLs jointly influence serum ACE levels in this population. One QTL is located within or close to the ACE locus and explains 27% of the total variability; the second QTL is unlinked to the ACE locus and explains 52% of the variability. The identification of the molecular mechanisms underlying both QTLs is necessary in order to interpret the role of ACE in cardiovascular disease.

Analysis of Variance↗
PubMed1994

Multiple DNA variant association analysis: application to the insulin gene region in type I diabetes.

Association and linkage studies have shown that at least one of the genetic factors involved in susceptibility to insulin-dependent diabetes mellitus (IDDM) is contained within a 4.1-kb region of the insulin gene. Sequence analysis has led to the identification of 10 DNA variants in this region that are associated with increased risk for IDDM. These variants are in strong linkage disequilibrium with each other, and previous studies have failed to distinguish between the variant(s) that cause increased susceptibility to IDDM and others that are associated with the disease because of linkage disequilibrium. To address this problem, we have undertaken a large population study of French diabetics and controls and have analyzed genotype patterns for several of the variant sites simultaneously. This has led to the identification of a subset consisting of four variants (-2733AC, -23HphI, -365VNTR, and +1140AC), at least one of which appears to be directly implicated in disease susceptibility. The multiple-DNA-variant association-analysis approach that is applied here to the problem of identifying potential susceptibility variants in IDDM is likely to be important in studies of many other multifactorial diseases.

Diabetes Mellitus, Type 1↗
PubMed1993

Genetic analysis of diabetes and insulitis in an interspecific cross of the nonobese diabetic mouse with Mus spretus.

The nonobese diabetic (NOD) mouse is a widely used model for genetic studies of insulin-dependent diabetes mellitus due to the similarities between the murine and human diseases. To aid in the localization and identification of diabetes-related susceptibility genes, we have constructed an interspecific backcross between NOD and Mus spretus (SEG/Pas) mice. Although no diabetic animals were observed in the first backcross generation of (SEG/Pas x NOD) x NOD (BC1), the incidence of insulitis (lymphocyte infiltration of the islets of Langerhans) exceeded 20% after injections of cyclophosphamide, a treatment that provokes an acute form of diabetes in NOD mice. Insulitis, a prediabetic condition, is a useful phenotype in studies of diabetes susceptibility. In the second backcross (BC2) generation, 8% of the animals became diabetic and 76% were found to have insulitis. Genetic mapping studies in the BC2 families confirmed the importance of the major histocompatibility complex region on the severity of insulitis and suggested that additional susceptibility loci were linked to markers on mouse chromosomes 3, 6, and 15. Mus spretus crosses have been an important tool in recent advances in murine genetics, and our results extend their usefulness to the study of a multifactorial disease.

Animals↗
PubMed1993

Systematic study of human alpha beta T cell receptor V segments shows allelic variations resulting in a large number of distinct T cell receptor haplotypes.

The variation of the alpha beta T cell receptor (TCR) results mainly from rearrangements of germ-line V, D and J elements combined with the processes of N- and P-region addition. In addition to this extensive diversity, diallelic polymorphism is also recognized in V regions of beta loci. Four such polymorphisms have previously been defined, but the full extent of such variation has not yet been established. To investigate allelic polymorphism, we used a strategy based V locus-specific polymerase chain reaction and single-strand conformation polymorphisms. Studying the two V beta 2 loci and the V alpha 8.1 locus, we found that all exhibited a coding polymorphism. One of the V beta 2 loci proved to be the first multiallele segment to be recognized, with three common variants. The second V beta 2 locus, for which none of the two alleles has been identified in cDNA, appeared in fact to be a V beta orphon, in abnormal location on the chromosome 9. A yeast artificial chromosome containing part of the TCRB locus allowed us to place the first V beta 2 segment on the known map to define haplotypes with two other polymorphic segments: V beta 1 and V beta 6.7. Multiple distinct haplotypes result from combinations between these polymorphic loci, showing that V beta regions are highly variable between individuals. Two alleles exist at the V alpha 8.1 segment and both are expressed. This represents the first example of a frequent coding polymorphism for TCRA gene. The distribution of allele frequencies for these segments suggest the action of balancing selection. These data add a further dimension to TCR polymorphism and suggest new candidates to explore TCR-encoded susceptibility to autoimmune diseases.

Alleles↗
PubMed1993

A radiation hybrid map of human chromosome 11q22-q23 containing the ataxia-telangiectasia disease locus.

We describe a high-resolution radiation hybrid map of human chromosome 11q22-q23 containing the ataxia-telangiectasia (AT) disease gene loci. The order and intermarker distances of 32 chromosome 11q22-q23 markers were determined by a multipoint maximum likelihood method of analysis of the cosegregation of markers in 100 radiation hybrids. The radiation hybrid map of polymorphic loci was consistent with genetic linkage maps of common markers. Several genes, including alpha B-crystallin, adrenal ferrodoxin, CBL2, collagenase, dopamine receptor type 2, neural cell adhesion molecule, progesterone receptor, and stromelysins 1 and 2, were placed in relation to previously ordered, genetically mapped polymorphic loci. Five new markers (alpha B-crystallin, adrenal ferrodoxin, CJ52.114, CJ52.3, and D11S535) were ordered within the current published flanking markers for the AT group A and group C disease loci. A candidate AT group D gene (ATDC) identified by Kapp et al. (1992, Am. J. Hum. Genet. 51: 45-54) was mapped telomeric to THY1, outside the flanking markers identified by multipoint linkage analysis for the major AT locus.

Animals↗
PubMed1993

Genetic mapping through the use of synthetic tandem repeats in the mouse genome.

Polymers of arbitrary oligonucleotides can be used to detect polymorphic loci in a wide range of vertebrate genomes. Using 60 such probes, we previously reported the selection of the most efficient STR probes for polymorphism detection in the set of genomes investigated. We now report the use of this selection for the mouse genome and its contribution to genetic mapping. Twenty-three synthetic tandem repeats (STRs) sequences were probed on a recombinant inbred panel C57B1/6 x DBA/2. The loci detected are distributed in 70 linkage groups; 42 of these groups, corresponding to about 100 different polymorphic loci, include reference markers. These linkage groups appear to be evenly distributed within all the 20 mouse chromosomes with apparently no bias of repartition towards telomeres or centromeres.

Animals↗
PubMed1993

Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR.

Recent studies have demonstrated that a locus at 11p15.5 confers susceptibility to insulin dependent diabetes mellitus (IDDM). This locus has been shown to lie within a 19 kb region. We present a detailed sequence comparison of the predominant haplotypes found in this region in a population of French Caucasian IDDM patients and controls. Identification of polymorphisms both associated and unassociated with IDDM has allowed us to define further the region of association to 4.1 kb. Ten polymorphisms within this region are in strong linkage disequilibrium with each other and extend across the insulin gene locus and the variable number tandem repeat (VNTR) situated immediately 5' to the insulin gene. These represent a set of candidate disease polymorphisms one or more of which may account for the susceptibility to IDDM.

Base Sequence↗
PubMed1993

Schizophrenia-associated chromosome 11q21 translocation: identification of flanking markers and development of chromosome 11q fragment hybrids as cloning and mapping resources.

Genetic linkage, molecular analysis, and in situ hybridization have identified TYR and D11S388 as markers flanking the chromosome 11 breakpoint in a large pedigree where a balanced translocation, t(1;11)(q43;q21), segregates with schizophrenia and related affective disorders. Somatic cell hybrids, separating the two translocation chromosomes from each other and from the normal homologues, have been produced with the aid of immunomagnetic sorting for chromosome 1- and chromosome 11-encoded cell-surface antigens. The genes for two of these antigens map on either side of the 11q breakpoint. Immunomagnetic bead sorting was also used to isolate two stable X-irradiation hybrids for each cell-surface antigen. Each hybrid carries only chromosome 11 fragments. Translocation and X-irradiation hybrids were analyzed, mainly by PCR, for the presence of 19 chromosome 11 and 4 chromosome 1 markers. Ten newly designed primers are reported. The X-irradiation hybrids were also studied cytogenetically, for human DNA content, by in situ Cot1 DNA hybridization and by painting the Alu-PCR products from these four lines back onto normal human metaphases. The generation of the translocation hybrids and of the chromosome 11q fragment hybrids is a necessary preliminary to determining whether a schizophrenia-predisposition gene SCZD2 is encoded at this site.

Animals↗
PubMed1993

Localization of juvenile, but not late-infantile, neuronal ceroid lipofuscinosis on chromosome 16.

The neuronal ceroid lipofuscinoses (NCL) are a group of progressive neurodegenerative disorders characterized by the deposition of autofluorescent proteinaceous fingerprint or curvilinear bodies. We have found that CLN3, the gene underlying the juvenile form of NCL, is very tightly linked to the dinucleotide repeat marker D16S285 on chromosome 16. Integration of D16S285 into the genetic map of chromosome 16 by using the Centre d'Etude du Polymorphisme Humain panel of reference pedigrees yielded a favored marker order in the CLN3 region of qtel-D16S150-.08-D16S285-.04-D16S148-.02-D16S 67-ptel. The most likely location of the disease gene, near D16S285 in the D16S150-D16S148 interval, was favored by odds of greater than 10(4):1 over the adjacent D16S148-D16S67 interval, which was recently reported as the minimum candidate region. Analysis of D16S285 in pedigrees with late-infantile NCL virtually excluded the CLN3 region, suggesting that these two forms of NCL are genetically distinct.

Adolescent↗
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↗