ABSTRACT
Anxiety disorders are complex and common psychiatric illnesses associated with considerable morbidity and social cost. We have studied the molecular basis of the cooccurrence of panic and phobic disorders with joint laxity. We have identified an interstitial duplication of human chromosome 15q24-26 (named DUP25), which is significantly associated with panic/agoraphobia/social phobia/joint laxity in families, and with panic disorder in nonfamilial cases. Mosaicism, different forms of DUP25 within the same family, and absence of segregation of 15q24-26 markers with DUP25 and the psychiatric phenotypes suggest a non-Mendelian mechanism of disease-causing mutation. We propose that DUP25, which is present in 7% control subjects, is a susceptibility factor for a clinical phenotype that includes panic and phobic disorders and joint laxity.
Subject(s)
Chromosomes, Human, Pair 15/genetics , Gene Duplication , Genetic Predisposition to Disease/genetics , Joint Instability/genetics , Panic Disorder/genetics , Phobic Disorders/genetics , Polymorphism, Genetic/genetics , Adult , Alleles , Female , Gene Dosage , Genes, Duplicate/genetics , Humans , In Situ Hybridization, Fluorescence , Interleukin-16/genetics , Joint Instability/complications , Lod Score , Male , Microsatellite Repeats/genetics , Mosaicism/genetics , Mutation/genetics , Panic Disorder/complications , Pedigree , Penetrance , Phobic Disorders/complications , Physical Chromosome Mapping , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
The expression of transgene loci in mammals often occurs in a heterocellular fashion resulting in variegated patterns of expression. We have examined the effect of chromosomal integration site, copy number, and transcriptionally activating sequences on the variegation of a keratin 5-lacZ (K5Z) construct in the stratified epithelia of transgenic mice. lacZ expression in these mice is always mosaic, and the beta-gal activity per cell is usually higher in the lines with a higher proportion of expressing cells. Similar constructs, in which cDNAs were exchanged by lacZ sequences, showed no variegation. Also, when a strongly active, nonvariegating construct was coinjected with K5Z, most transgenic lines showed an almost homogeneous lacZ expression. The comparison of transgene arrays of different copies inserted at the same locus (obtained by using a lox/Cre system) showed that the reduction of copy number does not lead to an increase in the proportion of cells that express the transgene. Finally, in most of the variegating or nonexpressing lines the transgenes were located both at intermediate positions and at peritelomeric regions in the long chromosome arms. These findings suggest that the probability and efficiency of expression of K5Z genes depend on both long range chromosomal influences and on sequences in the transgene array.
Subject(s)
Keratins/genetics , Lac Operon , Animals , Blotting, Northern , Blotting, Southern , Chromosome Mapping , DNA, Complementary , Epithelium/metabolism , Gene Expression , In Situ Hybridization, Fluorescence , Mice , Mice, Transgenic , TransgenesABSTRACT
Centromere-specific DNA probes for chromosomes 4, 7 and 18 were used to simultaneously analyze chromosome loss, non-disjunction, breaks within the labeled region, and nucleoplasmic bridges induced by gamma rays in binucleated human lymphocytes. The doses used were 0, 1, 2 and 4 Gy, and approximately 1000 cells were scored per dose. Micronucleus frequency increased in a linear-quadratic fashion. For chromosome loss, significant increases were observed at 2 and 4 Gy, whereas for non-disjunction significant increases were observed at 1 Gy; thus non-disjunction allowed us to detect the effects of radiation at a lower dose than chromosome loss. The use of centromere-specific probes allowed discrimination between the clastogenic and aneugenic effects of ionizing radiation. The analysis of chromosome loss, not taking fragmented signals into account, ensures the detection of an aneugenic effect, which was not possible using pancentromeric probes. The frequency of chromosome breakage within the labeled regions was higher in nuclei than in micronuclei, suggesting an increase in the engulfment of chromosomal material by nuclei as a consequence of the presence of cytochalasin B in the cultures. Chromatin filaments connecting main nuclei, the so-called nucleoplasmic bridges, were observed in irradiated samples, and are a manifestation of rearranged chromosomes producing anaphase bridges.
Subject(s)
Centromere , Lymphocytes/radiation effects , Nondisjunction, Genetic , Dose-Response Relationship, Radiation , Gamma Rays , Humans , In Situ Hybridization, Fluorescence , Lymphocytes/ultrastructure , Micronucleus TestsABSTRACT
Fluorescent in situ hybridization using three chromosome-specific centromeric human DNA probes was used to analyze the aneuploidy frequency in human-hamster two-cell embryos. With these techniques first mitotic division errors due to the effects of physical or chemical agents on human spermatozoa, such as non-disjunction and anaphase lag, can be easily detected. In control samples the estimated frequency of non-disjunction and anaphase lag was 3.4%. This assay can also detect premeiotic or meiotic errors. We estimated the same frequency (3.4%) for disomy, whereas monosomy was not found.