Defective mismatch repair has recently been implicated as the major contributor towards the mutator phenotype observed in tumour cell lines derived from patients diagnosed with hereditary non-polyposis colon cancer (HNPCC). Cell lines from other cancer-prone syndromes, such as xeroderma pigmentosum, have been found to be defective in nucleotide excision repair of damaged bases. Some genetic complementation groups are defective specifically in transcription-coupled excision repair, although this type of repair defect has not been associated with cancer proneness. Mechanisms contributing to the high incidence of activating point mutations in oncogenes (such as H-ras codon 12) are not understood. It is possible that novel mechanisms of misrepair or misreplication occur at these sites in addition to the above DNA repair mechanisms. In this study, we have compared the rate of strand-directed mismatch repair of four mispairs (G:A, A:C, T:C and G:T) at the H-ras codon 12, middle G:C position. Our results indicate that, although this location is not a 'hot spot' for bacterial mismatch repair, it is a 'hot spot' for decreased repair of specific mismatched bases within NIH 3T3 cells. NIH 3T3, unlike Escherichia coli, have an extremely low repair rate of the G:A mispair (35%), as well as the A:C mispair (58%) at this location. NIH 3T3 also have a moderately low repair rate of the T:C mispair (80%) at the codon 12 location. Conversely, NIH 3T3 repair of G:T (100%) is comparable to E. coli repair (94%) of this mismatch. These results demonstrate that a mismatch containing an incorrect adenine on either strand at the H-ras codon 12 middle base pair location is most likely to undergo a mutational event in NIH 3T3 cells. Conversely, a mismatch containing an incorrect thymine in the transcribed strand is least likely to undergo a mutational event.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with significant morbidity and mortality, characterized by remarkable clinical variability with unknown etiology. Genetic contribution to the development of SLE is well established. Recently, we found evidence (Po0.004) of linkage at 16p13 and 16q12 -13 in a genome scan based on 37 Hispanic families. The main objective of this study is to replicate and confirm the linkage at these two genomic locations in two large independent replication data sets designated as, group-1 and group-2, consisting of 172 and 120 multiplex SLE families, respectively. We have found a significant evidence of linkage with high heterogeneity (HLOD ¼ 4.85, a ¼ 35%) at 16q12-13 in group-2. Other independent research groups also reported the SLE susceptibility at or close to 16q12-13 previously. Therefore, independent published reports, together with our initial linkage with Hispanics and followed by significant evidence from group-2, provide a strong and confirmed evidence for an SLE susceptibility locus at 16q12 -13.

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PurposeThe Gullah population has a very low level of European admixture and has higher homogeneity in terms of environmental and genetic influences. The incidence of systemic lupus erythematosus (SLE) is high and the clinical manifestations of Gullah SLE patients are also often severe. Therefore, such characteristics may help us identify more easily, through gene expression microarrays, the genes involved in the pathogenesis of SLE. We studied gene expression in Epstein-Barr virus transformed B cell lines derived from Gullah SLE patients and matched unrelated controls to identify candidate genes or pathways important in the development of lupus.Methods6 Gullah SLE patients were selected according to American College of Rheumatology (ACR) criteria for SLE. 6 controls were matched by age, sex, race, and state of residence. Human genome U133 plus 2.0 arrays (Affymetrix) were used for each subject. Gene expression differences were evaluated for genes with p < .05 for the paired t-test, p < .0001 for the associative t-test, and an apparent ratio of expression of > 2.0 or < 0.5.ResultsTwo separate independent tests of these 6 pairs were done. The consistency between these two tests is 62%. Samples from the Gullah lupus patients differently expressed 299 genes when compared to controls (284 up-regulated, 15 downregulated). The differentially expressed genes include small nuclear ribonucleotide proteins, apoptosis pathway members, signal transduction pathway members, and ubiquitin specific protease related genes. Several genes are located in lupus susceptibility loci.ConclusionsDifferential gene expression analysis of cell lines derived from Gullah lupus patients and controls has allowed us to identify promising candidate genes and associated pathways that promise to be important to understanding lupus.

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