摘要:

Gilles de la Tourette syndrome (GTS) and related disorders such as chronic multiple tics and obsessive compulsive behaviour are likely to be genetically transmitted with a Mendelian autosomal dominant mode of transmission. Following our discovery of a patient with GTS who also carried a balanced translocation 46 XY, t(3:8) (p21.3 q24.1), a linkage study of several families was performed covering the areas on chromosomes 3 and 8 implicated by the cytogenetic abnormality in this unique GTS patient. A positive multipoint lod score of 2.9 was obtained on chromosome 3 with markers at the loci RAF1, THRB, and D3S11. Subsequently, the genetic map of this region was improved and new polymorphic markers close to our original three markers were identified. With the new map the maximum two-point lod with any marker was reduced to 1.77 at RAF1, and the FASTMAP approximate multipoint lod excluded the likely region of the breakpoint. After constructung a somatic cell hybrid, the original three markers were mapped relative to the break point of the translocation and to other new markers. It was confirmed that the original markers were at least 20 cM away from the position of the break point. In addition, we traced further family members of our translocation GTS proband, and identified affected individuals who did not possess the translocation. We concluded that the translocation was not responsible for the GTS symptoms in our affected proband.

ISSN:0955-8829    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

It was previously reported that selection for differences in the hypothermic effects to the selective 5-HT-1A agonist, 8-OH-DPAT, occurred rapidly, with very substantial differences present by the fourth generation. The present communication summarizes the findings from the next five generations of selection and from behavioral and other functional studies on these rats. The rats which were more sensitive to 8-OH-DPAT (High DPAT Sensitive – HDS) exhibited decreases in temperature of 4°C or more and the distribution did not overlap with that of the rats which were less sensitive to 8-OH-DPAT (Low DPAT Sensitive – LDS) which exhibited decreases in temperature of 1.5°C or less. The randomly bred control group (Random DPAT Sensitive – RDS) exhibited intermediate temperature decreases (means of 1.6–1.8°C), with some overlap with the distributions of the selected groups. Pretreatment with pindolol, a 5-HT-1A antagonist, reduced the hypothermic response to 8-OH-DPAT, but pretreatment with ritanserin, a 5-HT-7 and 5-HT-2A/C antagonist, had no effect, confirming that the hypothermic response to 8-OH-DPAT is mediated predominantly by 5-HT-1A receptors. The HDS rats were less mobile in a forced swim test and drank more saccharin solution in a two-bottle choice paradigm than the LDS or RDS rats over several generations. In contrast, there were no consistent differences among the groups for open field activity or performance in an elevated plus maze. There were no differences among the groups for voluntary alcohol intake, but the HDS rats exhibited greater suppression of alcohol and saccharin intake after injection of 8-OH-DPAT (0.125 mg kg−1). The HDS rats were also found to have a higher number of 5-HT-1A binding sites in cortical regions than the LDS or RDS rats, but there were no 5-HT-1A binding site differences in the raphe nuclei. These findings clearly show that consistent behavioral differences do occur in the 8-OH-DPAT-selected lines of rats, but only for behaviors related to possible depression or reward, not anxiety. The pattern of binding results suggests that these behavioral correlates of 8-OH-DPAT selection may be related to changes in cortical 5-HT-1A receptors rather than raphe autoreceptors.

ISSN:0955-8829    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Although serotonergic dysregulation is a leading pathogenetic hypothesis for obsessive-compulsive disorder (OCD), some evidence also suggests a possible dysregulation of the dopaminergic system in this disorder. Therefore, individual differences in deoxyribonucleic acid (DNA) coding for dopamine receptor proteins might contribute to the genetic background of this disorder. Previously we reported a null mutation in exon 1 of the dopamine D4 receptor gene. The variant type is characterized by a 13 bp deletion and is predicted to code for a truncated, non-functional receptor. We assessed the frequency of this polymorphism in 157 OCD patients, 196 schizophrenics. 111 bipolars and 162 healthy controls of Italian descent. Our findings do not implicate a role for this mutation in conferring a susceptibility to OCD and confirm previous negative results regarding its involvement in schizophrenia and bipolar disorder.

ISSN:0955-8829    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Linkage of bipolar disease to several markers mapping to chromosome 4p has been reported in an extended family multiply affected with bipolar affective disorder and no linkage was found at other locations with 106 microsatellite markers, of which 58 were dinucleotide and 48 tetranucleotide repeats [Blackwood et al. (1996), Nature Genetics, 12, 427–430]. Collecting these data provided the opportunity to assess the usefulness and accuracy of the automated linkage preprocessor (ALP) programme in a linkage study and to make a detailed comparison of di- and tetranucleotides with this semi-automated system. Genotypes were acquired using the automated linkage preprocessor (ALP) without any manual intervention at any stage of the procedure and results of analyses of these data were compared with results based on genotypes checked by visual inspection of the data. The ALP program was found to be timesaving and reliable and yielded similar results to non-automated reading using both di- and tetranucleotide repeat microsatallite markers. Tetranucleotides had fewer errors due to multiple genotypes and a lower incidence of stutter peaks making them more informative than dinucleotides in this linkage study.

ISSN:0955-8829    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Catechol-O-methyl transferase (COMT) metabolizes a variety of catecholamines such as dopamine, adrenaline and nor-adrenaline. It exists in common high and low activity forms. The low activity form is the result of an amino acid substitution (val-108-met) which reduces the thermostability of the enzyme [Lotta et al. (1994) Biochemistry, 34, 4202–4210]. We have genotyped this polymorphism in 178 trios consisting of Han Chinese schizophrenic subjects and their parents in order to test the hypothesis that the high activity allele is transmitted more often to affected subjects. The data were analysed using the transmission disequilibrium test (TDT), a robust method of detecting linkage in the presence of allelic associations. Of the 131 parents heterozygous at this locus, 80 transmitted the high activity allele (val-108) to affected offspring, while the remaining 51 transmitted the low activity allele (p = 0.005, one-tailed). Combining this result with that of a previous TDT study of the same polymorphism in familial schizophrenia [Kunugi et al. (1996) submitted] gives significant evidence for linkage disequilibrium (p = 0.0015). However, val-108 is frequent in the Han Chinese population, and in the present sample, 239 of the 350 non-transmitted parental alleles were val-108 (68%). It is therefore unlikely that val-108 allele of COMT has a major effect on susceptibility to schizophrenia. Our results suggest that either val-108 is a minor risk factor for schizophrenia, that the COMT gene has additional polymorphisms with greater effect on risk, or that this region of chromosome 22 contains a susceptibility gene which is in linkage disequilibrium with the COMT gene.

ISSN:0955-8829    

出版商:OVID    

年代:1996

数据来源: OVID

ISSN:0955-8829    

出版商:OVID    

年代:1996

数据来源: OVID

ISSN:0955-8829    

出版商:OVID    

年代:1996

数据来源: OVID

ISSN:0955-8829    

出版商:OVID    

年代:1996

数据来源: OVID

ISSN:0955-8829    

出版商:OVID    

年代:1996

数据来源: OVID

ISSN:0955-8829    

出版商:OVID    

年代:1996

数据来源: OVID