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T Flint

Publications and source records attributed to T Flint.

At least 19 recordsLinked to original sources
PubMed2002

A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22-21, 4p16, 6q14-22, 10q26 and 16p13.3.

The present study reports a genomewide scan using linkage analysis for risk genes involved in bipolar disorder with 613 microsatellite markers including additional testing of promising regions. As previously published significant linkage was obtained at chromosome 12q24.3 with a two-point parametric lod score of 3.42 at D12S1639 including all members in both families (empirical P-value 0.00004, genome-wide P-value 0.0417). The multipoint parametric lod score at D12S1639 was 3.63 (genome-wide P-value 0.0265). At chromosome 1p22-p21 a parametric, affecteds-only two-point lod score of 2.75 at marker D1S216 was found (empirical P-value 0.0002, genome-wide P-value 0.1622). A three-point lod score of 2.98 (genome-wide P-value 0.1022) at D1S216, and a multipoint non-parametric analysis with a maximum NPL-all score of 17.60 (P-value 0.00079) at D1S216 further supported this finding. A number of additional loci on chromosomes 4p16, 6q14-q22, 10q26 and 16p13.3 yielded parametric lod scores around or above 2.

Bipolar Disorder↗
PubMed1998

A functional variant of the serotonin transporter gene in families with bipolar affective disorder.

BACKGROUND: The serotonin transporter protein (SERT) reuptakes serotonin from synapses and has been implied as the site of therapeutic action of many antidepressant drugs. SERT is one of the most relevant candidate genes for bipolar affective disorder. Recently a functionally important 44 basepair deletion in the regulatory region of the SERT gene was described. Association between this variant and affective disorder has been suggested. METHODS: The present study analysed this variation and another variation in the SERT gene and nearby DNA markers in order to test for linkage between SERT and bipolar affective disorder in two Danish families. RESULTS AND CONCLUSION: There was no evidence that variants in the SERT gene were a stronger dominant disease gene for the development of affective disorder in the families. The possibility of a recessive disease gene at or near SERT could not be excluded. LIMITATIONS: The present study cannot exclude if variations at or near the SERT gene were weak susceptibility genes or determine if they are important for other characteristics than presence or absence of disease. CLINICAL RELEVANCE: Further studies of the SERT gene in affective and other disorders, as well as in relation to treatment response to antidepressants are needed.

Bipolar Disorder↗
PubMed1997

Refined localization of the pyruvate dehydrogenase E1 alpha gene (PDHA1) by linkage analysis.

Pyruvate dehydrogenase (PDH) E1 alpha is a key component in the PDH complex which catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. Defects in the gene coding for PDH E1 alpha (PDHA1) are associated with a variety of clinical symptoms, often of a severe character. In the present study, the segregation of three polymorphic CA repeats located in PDHA1 was followed in the 40 CEPH reference pedigrees. Using these data, multipoint linkage analysis was carried out, refining the genetic location of PDHA1. The 16-point map presented locates PDHA1 in an approximately 3-cM interval between DXS999 and DXS365 with odds of more than 1000:1. From known physical localizations of the flanking marker loci, PDHA1 could be regionally assigned to Xp22.1-p22.2. The information provided should be of value in clinical settings.

Chromosome Mapping↗
PubMed1996

Linkage study between manic-depressive illness and chromosome 21.

Chromosome 21, of interest as potentially containing a disease gene for manic-depressive illness as possible evidence for a gene pre-disposing to affective disorder, has recently been reported in a single large family as well as samples of families. The present study investigates for linkage between manic-depressive illness and markers covering the long arm of chromosome 21 in two manic-depressive families, using ten microsatellite polymorphisms as markers. No conclusive evidence for a disease gene on the long arm of chromosome 21 was found. Assuming either a dominant or recessive mode of inheritance, close linkage to the marker PFKL, which has been reported as possibly linked to affective disorder, seems unlikely in the families studied here. PFKL and more telomeric markers yielded small positive lod scores at higher recombination fractions in the largest family, and small positive lod scores at lower recombination fractions in the affected-only analyses in the smallest family.

Bipolar Disorder↗
PubMed1996

Assignment of the human tryptophanyl-tRNA synthetase gene (WARS) to chromosome 14q32.2 --> q32.32.

Tryptophanyl-tRNA synthetase catalyzes the aminoacylation of tRNAtrp with tryptophan, an essential function in the cell's protein synthesis machinery. It has been shown that tryptophanyl-tRNA synthetase is induced by interferon, and this has led to hypotheses about other possible functions of tryptophanyl-tRNA synthetase. We have mapped a cDNA probe of the tryptophanyl-tRNA synthetase gene (WARS) by a combination of somatic cell hybrid analysis, fluorescence in situ hybridization (FISH), and linkage analysis. Both FISH and linkage analysis independently supported a more distal position of WARS than had been previously reported. FISH mapping indicated a most likely location at 14q32.31. Linkage analysis was based on the 40 reference families from the CEPH collaboration and resulted in a 13-point map, placing WARS, with odds of more than 1,000:1, within an area of approximately 10 cM and, with odds of 198:1, in an approximately 6 cM interval between pCMM101 and D14S27. The study provides additional integration of the physical and genetic maps of the distal part of 14q, as well as genetic tools enabling a more complete understanding of the function of tryptophanyl-tRNA synthetase, especially with regard to the cryptic inducibility of interferon.

Chromosome Mapping↗
PubMed1995

Linkage analysis between manic-depressive illness and markers on the long arm of chromosome 11.

The long arm of chromosome 11 is one of the most interesting regions in the search for major genes involved in the etiology of manic-depressive illness. Several candidate genes have been identified, including the gene encoding the dopamine D2 receptor, the M1 muscarinic receptor, and porfobillinogen deaminase. Furthermore, different families with co-segregation of psychiatric illness and structural chromosome abnormalities involving regions 11q21, 11q22.3, and 11q25 have been reported. Using narrow as well as broad phenotypic models, conservative genetic parameters, models with dominant or recessive modes of inheritance, and various methods to reduce misclassification, the present study did not find evidence for a major gene causing manic-depressive illness on the long arm of chromosome 11. In the broader phenotypic models multi-point analyses excluded at least 11q14 to 11q23.3, approximately 60 cM, even in one large family. Assuming homogeneity close linkage to DRD2 was excluded for all dominant models, and also in the affecteds-only analyses in the large family alone.

Biomarkers↗
PubMed1995

Cloning, expression, and chromosome mapping of human galectin-7.

The galectins are a family of beta-galactoside-binding proteins implicated in modulating cell-cell and cell-matrix interactions. Here we report the cloning and expression of a novel member of this family (galectin-7) that correspond to IEF (isoelectric focusing) 17 (12,700 Da; pI, 7.6) in the human keratinocyte protein data base, and that is strikingly down-regulated in SV40 transformed keratinocytes (K14). The cDNA was cloned from a lambda gt11 cDNA expression library using degenerated oligodeoxyribonucleotides back-translated from an IEF 17 peptide sequence. The protein encoded by the galectin-7 clone comigrated with IEF 17 as determined by two-dimensional (two-dimensional gel electrophoresis) analysis of proteins expressed by transiently transfected COS-1 cells, and bound lactose. Alignment of the amino acid sequences with other members of the family showed that the amino acids central to the beta-galactoside interaction are conserved. Galectin-7 was partially externalized to the medium by keratinocytes although it has no typical secretion signal peptide. Immunoblotting as well as immunofluorescence analysis of human tissues with a specific galectin-7 antibody revealed a narrow distribution of the protein which was found mainly in stratified squamous epithelium. The antigen localized to basal keratinocytes, although it was also found, albeit at lower levels, in the suprabasal layers where it concentrated to areas of cell to cell contact. Both, its cellular localization as well as its striking down-regulation in K14 keratinocytes imply a role in cell-cell and/or cell-matrix interactions necessary for normal growth control. The galectin-7 gene was mapped to chromosome 19.

Adult↗
PubMed1995

Refined mapping of the psoriasin gene S100A7 to chromosome 1cen-q21.

Psoriasin is a low molecular weight protein of the S100 family, which is highly upregulated in psoriatic epidermis, and whose function is related to skin inflammatory responses. We have applied a cDNA probe from the corresponding psoriasin gene S100A7 in a refined localisation analysis. S100A7 was mapped physically by human/rodent somatic cell hybrid analysis, and more precisely genetically by multilocus linkage analysis of 40 CEPH (Centre d'Etude du Polymorphisme Humain) families. The resulting 12-point linkage map was supported by odds of at least 1000:1, where S100A7 could be placed with a multipoint lodscore of 27.4 in an approximately 7-cM interval. The order of the 12 loci was as follows (with the best estimates of recombination frequencies given in between): AMY2B-0.091-D1S73(0.039)-D1S11(-0.053)-D1S189(-0 .017)-D1S1252 (-0.017)-D1S13(-0.078)-D1Z5(-0.051)-S100A7(-0.022)- MUC1(-0.026)-SPTA1 (-0.066)-ATP1A2(-0.014)-APOA2. Furthermore, from this map S100A7 could be assigned to the regional position of chromosome 1cen-q21. The linkage information presented should be of great value in association and linkage studies of diseases where psoriasin, or some of the several other very closely linked and functionally related genes, are seen as candidate genes, e.g. in psoriasis.

Calcium-Binding Proteins↗
PubMed1995

A possible locus for manic depressive illness on chromosome 16p13.

We have previously reported possible evidence for linkage between manic depressive illness and the locus at 16p13.3 encoding the enzyme phosphoglycolate phosphatase (PGP), in the larger of two Danish families. As PGP was not fully informative, 12 additional DNA markers were tested in these families to clarify if a gene involved in the etiology of manic depressive illness might be located on chromosome 16p13. Though not reaching a lod score level of 3.0, the possible presence of a disease gene for manic depressive illness on chromosome 16p13 was still suggested. The evidence for a dominant locus near PGP was weakened. However, when assuming a recessive mode of inheritance and including both families a two-point lod score of 2.52 was found for marker D16S510, and a three-point lod score of 2.65 in both families combined and 2.29 in the large family alone was obtained in the same area. Simulations indicated that lod scores as obtained for several markers in the large family alone, would occur only rarely with an unlinked marker.

Bipolar Disorder↗
PubMed1995

No evidence of linkage between manic depressive illness and the dopa decarboxylase gene or nearby region on chromosome 7p.

Dopa decarboxylase (DDC) is involved directly in the synthesis of dopamine and serotonin and indirectly in the synthesis of noradrenaline. The present study investigated two Danish families for linkage between manic depressive illness, a marker at the DDC locus which has been mapped to 7p11-p13 and 10 microsatellite markers covering chromosome 7q11-p15. No evidence of linkage was found assuming a dominant or a recessive mode of inheritance. We have earlier reported evidence against linkage between manic depressive illness and tyrosine hydroxylase and dopamine beta-hydroxylase. Mutations of major importance in the genes encoding the three enzymes involved in the synthesis of dopamine and noradrenaline seem less likely in the families we have studied. Further investigations of genetic and other pathophysiological mechanisms in relation to the monoamine hypotheses for manic depressive illness are still of relevance. There is a need for further linkage and association studies as well as a search for possible mutations in the relevant genes involved in the monoaminergic pathways to clarify their possible role in the aetiology of manic depressive illness.

Bipolar Disorder↗
PubMed1994

Linkage analysis between manic depressive illness and the dopamine beta-hydroxylase gene.

The dopamine beta-hydroxylase (DBH) gene is a candidate gene in manic depressive illness. DBH is required for conversion of dopamine to norepinephrine, the third step in catecholamine biosynthesis. A few earlier linkage studies have found low to moderately positive lod scores in manic depressive families for ABO which is closely linked to DBH. Based on several studies an association between manic depressive illness and ABO blood type has been suggested. Mutations at the DBH locus might thus be involved in the etiology of manic depressive illness in some families. The DBH gene is reported here as unlikely to be a major gene causing manic depressive illness in a large family. Linkage was excluded assuming a dominant mode of transmission. Several methods were used to minimize misclassification.

Bipolar Disorder↗
PubMed1994

Linkage analysis between manic depressive illness and the region on chromosome 12q involved in Darier's disease.

Co-segregation between Darier's disease and manic depressive illness has been reported. A gene causing Darier's disease has recently been mapped to chromosome 12q23-q24.1, and this region may thus be considered a candidate region potentially containing a gene involved in the aetiology of manic depressive illness. At least one possible candidate gene for manic depressive illness, pro-melanin-concentrating hormone, is located on chromosome 12q23-q24. The present study investigated linkage between manic depressive illness and this region on chromosome 12q, using three microsatellite polymorphisms as genetic markers which flank the gene causing Darier's disease. For all dominant models close linkage was excluded. For broader phenotypic models linkage was excluded in the interval between markers, even in one large family alone.

Bipolar Disorder↗
PubMed1994

Exclusion of linkage between manic depressive illness and tyrosine hydroxylase and dopamine D2 receptor genes.

Mutations at the tyrosine hydroxylase or dopamine D2 receptor loci causing manic depressive illness are unlikely in two families reported here. Linkage was excluded for both loci assuming a dominant mode of transmission and for the tyrosine hydroxylase locus also assuming a recessive mode of transmission. The exclusion was significant using models based on severity of psychopathology and a model requiring severe illness also in first-degree relatives. Conservative genetic parameters were used to minimize misclassification.

Alleles↗
PubMed1994

Charcot-Marie-Tooth disease type 1A: the parental origin of a de novo 17p11.2-p12 duplication.

Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant peripheral neuropathy associated with a DNA duplication on chromosome 17p11.2-p12 in the majority of cases. Most of the sporadic cases are due to a de novo duplication. We have screened for this duplication in 11 Danish patients with CMT type 1, using four different techniques, and identified a de novo duplication in a sporadic case. Analysis of the fully informative pVAW409R3a alleles in this family showed the duplication to be of paternal origin.

Adult↗
PubMed1992

The use of either the nose or outer ear as a means of determining the postmortem period of a human corpse.

Presented in this paper are the initial results involving the use of the nose or outer ear as temperature measurement sites to determine the postmortem period of the human corpse. Simple mathematical models for both sites are developed based on cooling curves of five corpses. Analysis of errors between actual and calculated postmortem intervals suggest that in its present form, the described methods would not be suitable for use in accurately determining the time since death of human corpses.

Body Temperature↗