Association study between the dopamine receptor D(4) gene and obsessive-compulsive disorder.

Pharmacological and neuroanatomical evidence suggest the involvement of the dopaminergic system in obsessive-compulsive disorder (OCD). Analysis of the 48-bp dopamine receptor D(4) (DRD4) gene polymorphism in a sample of 210 OCD patients and 202 healthy control subjects showed a significant association (chi(2)=27.5, df=6, p=0.0003). This difference was attributable to a lower frequency of allele 4R in OCD patients compared with the control group (chi(2)=9.33, p=0.0027). However, we did not replicate previous findings of an association between the 7R allele and OCD patients with tics. Finally, we analyzed a sub-sample of 86 OCD families. E-TDT analysis in 70 informative parents did not confirm the association observed in our case-control analysis. In conclusion, the current study cannot exclude an association between DRD4 gene and OCD in the largest sample analyzed. However, further studies will be required to confirm if the DRD4 gene is involved in the pathogenesis of this disorder.

A DNA repeat, NBL2, is hypermethylated in some cancers but hypomethylated in others.

Hypermethylation at certain CpG-rich promoters and hypomethylation at repeated DNA sequences are very frequently found in cancers. We provide the first report that a DNA sequence (NBL2) can be either extensively hypermethylated or hypomethylated in cancer. Previously, it was shown that NBL2, a complex tandem DNA repeat in the acrocentric chromosomes, is hypomethylated at NotI sites in >70% of neuroblastomas and hepatocellular carcinomas and in cells from ICF syndrome (DNMT3B-deficiency) patients. Unexpectedly, by Southern blot analysis of 18 ovarian carcinomas, 51 Wilms tumors, and various somatic control tissues, we found that >70% of the cancers exhibited large increases in methylation at HhaI sites in NBL2 compared with all the controls. In contrast, 17% of the carcinomas showed major decreases in methylation at HhaI and NotI sites. The intermediate levels of methylation at HhaI sites in somatic controls enabled this discovery of cancer-linked hypermethylation and hypomethylation in NBL2. In a comparison of ovarian epithelial carcinomas, low malignant potential tumors, and cystadenomas, NBL2 hypermethylation at HhaI sites was significantly related to the degree of malignancy, and hypomethylation was seen only in the carcinomas. By RT-PCR, we found NBL2 transcripts at low levels in a few cancers and undetectable in various normal tissues. In the tumors there was no association of NBL2 hypomethylation and transcription, but this may reflect NBL2's lack of identifiable promoter elements and our evidence for run-through transcription from adjacent sequences into NBL2. The propensity of NBL2 sequences to become either hypermethylated or hypomethylated in cancer suggests that these opposite epigenetic changes share an early step during carcinogenesis and that cancer-linked hypermethylation might be spontaneously reversible.

Imatinib (ST1571) provides only limited selectivity for CML cells and treatment might be complicated by silent BCR-ABL genes.

Very promising results have been obtained in clinical trials on chronic-phase chronic myeloid leukemia (CP-CML) patients treated with imatinib mesylate (IM; Gleevecr, STI571), a BCR-ABL tyrosine kinase inhibitor. However, we found that IM caused considerable inhibition of normal hematopoietic progenitor cells upon treating control bone marrow (BM) cultures. In vitro IM treatment gave a decrease in the yield and size of colonies from BM of untreated CP-CML patients that was only two to three times that from the normal samples. Moreover, about 30% of myeloid progenitors (CFU-GM) from CML BM still formed colonies in the presence of IM, most of which had BCR-ABL RNA. About half of these treated colonies also displayed methylation of the internal ABL Pa promoter, a CML-specific epigenetic alteration, which was used in this study as a marker for BCR-ABL translocation-containing cells. However, ~5-8% of the treated or the untreated CML BM-derived colonies had no detectable BCR-ABL RNA by two or three rounds of RT-PCR despite being positive for the internal standard RNA and displaying hallmarks of CML, either t(9;22)(q34;ql 1) or ABL Pa methylation. Our results indicate that IM is only partially specific for CML progenitor cells compared to normal hematopoietic progenitor cells and suggest that some CML cells may have a silent BCR-ABL oncogene that could interfere with therapy.

Importance sampling method of correction for multiple testing in affected sib-pair linkage analysis.

Using the Genetic Analysis Workshop 13 simulated data set, we compared the technique of importance sampling to several other methods designed to adjust p-values for multiple testing: the Bonferroni correction, the method proposed by Feingold et al., and naïve Monte Carlo simulation. We performed affected sib-pair linkage analysis for each of the 100 replicates for each of five binary traits and adjusted the derived p-values using each of the correction methods. The type I error rates for each correction method and the ability of each of the methods to detect loci known to influence trait values were compared. All of the methods considered were conservative with respect to type I error, especially the Bonferroni method. The ability of these methods to detect trait loci was also low. However, this may be partially due to a limitation inherent in our binary trait definitions.

Ulnar/fibular ray defect and brachydactyly in a family: a possible new autosomal dominant syndrome.

The ulnar-mammary syndrome (MIM 181450) includes postaxial ray defects, abnormalities of growth, delayed sexual development, and mammary and apocrine gland hypoplasia. Brachydactyly type E (MIM 113300) presents with shortening of the metacarpals and phalanges in the ulnar ray in association with moderately short stature. We describe a three-generation family with variable expression of ulnar/fibular hypoplasia, brachydactyly, ulnar ray defects and short stature. The proband had ulnar hypoplasia with missing IV-Vth fingers, fibular hypoplasia on the right, bilateral club feet, growth retardation, a hypoplastic mid-face, an ASD and hemangiomas. She had normal mammary tissue and normal sweating. The mother had short stature, midfacial hypoplasia, a hypoplastic ulna and hypoplasia of the IVth metacarpal (brachydactyly) on the right without other associated malformations. The maternal grandfather had mild bilateral fibular hypoplasia and midphalangeal brachydactyly of the IV-Vth toes. His sister had mild short stature and shortening of the IVth metacarpal of the left hand. Two-point linkage analysis with microsatellite markers spanning the Ulnar-Mammary locus at 12q24.1 did not confirm linkage. The patients may have a previously undescribed syndrome.

Family study of obsessive-compulsive disorder in a Mexican population

Twenty seven obsessive-compulsive disorder (OCD) patients were studied at the Instituto Mexic ano de Psiquiatría in Mexico City. This is the first sample of OCD patients studied in latin America. There was a significant sex ratio difference and a significant difference in the type of obsessions and complusions displayed by males and females. Co-morbidity data demostrated a high frequency of obsessive-compulsive personality disorders, depression, sexual abuse, suicidal attempts and neurological damage. Approximately one third of OCD cases demonstrated a positive family history. There was a higher than expected frequency of first degree relatives affected with OCD. IN addition, this study may support the hypothesis that OCD and tics are genetically related