Primary ciliary dyskinesia (PCD; MIM 242650) is an autosomal recessive disorder of ciliary dysfunction with extensive genetic heterogeneity. PCD is characterized by bronchiectasis and upper respiratory tract infections, and half of the patients with PCD have situs inversus (Kartagener syndrome). We characterized the transcript and the genomic organization of the axonemal heavy chain dynein type 11 (DNAH11) gene, the human homologue of murine Dnah11 or lrd, which is mutated in the iv͞iv mouse model with situs inversus. To assess the role of DNAH11, which maps on chromosome 7p21, we searched for mutations in the 82 exons of this gene in a patient with situs inversus totalis, and probable Kartagener syndrome associated with paternal uniparental disomy of chromosome 7 (patUPD7). We identified a homozygous nonsense mutation (R2852X) in the DNAH11 gene. This patient is remarkable because he is also homozygous for the F508del allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Sequence analysis of the DNAH11 gene in an additional 6 selected PCD sibships that shared DNAH11 alleles revealed polymorphic variants and an R3004Q substitution in a conserved position that might be pathogenic. We conclude that mutations in the coding region of DNAH11 account for situs inversus totalis and probably a minority of cases of PCD.

The mammalian AP-endonuclease APE1 is a ubiquitous and remarkably multifunctional protein. It plays a central role in the base excision repair (BER) pathway for repairing damaged bases and DNA single-strand breaks induced by reactive oxygen species and alkylating agents and also repairing AP sites that are generated spontaneously or after the excision of oxidized and alkylated bases by DNA glycosylases (12,40). APE1 was also shown to incise DNA 5Ј to oxidatively damaged bases including 5,6-dihydrothymidine and alpha-2Ј-deoxyadenosine in the nucleotide incision repair pathway (11,21). The deletion of the N-terminal 61 amino acid residues, which are dispensable for the AP-endonuclease activity, affected its incision activity as well (21, 28). Moreover, the ability of APE1 to incise DNA 5Ј to a bulky exocyclic adduct such as p-benozoquinone has also been reported (22). Besides its repair function, mammalian APE1 has two unique and apparently distinct transcriptional regulatory activities. It was independently identified as a reductive activator of c-Jun in vitro and named . Subsequently, several other transcription factors (including p53, NF-B, hypoxia-inducible factor 1-␣, PAX5, and PAX8) were also shown to be activated by APE1, presumably via the same redox process (13,31,55). A third and distinct function of APE1 as a trans-acting factor was discovered when APE1 was identified as being one of the regulatory proteins that binds to the negative Ca 2ϩ response elements (nCaRE-A and -B) in the Ca 2ϩ -dependent downregulation of the parathyroid hormone gene (48) and subsequently in the human renin gene (17). We later showed that human APE1 is acetylated at Lys6 and Lys7 by the histone acetyltransferase p300, both in vivo and in vitro, and that acetylation enhances APE1's binding to nCaRE-B, leading to the repression of the parathyroid hormone promoter (2). Our follow-up studies indicated that a small but significant fraction of APE1 in HeLa cells and mouse liver is present in the acetylated form (14,56). Recently, we have shown that the early growth response protein (Egr-1)-mediated activation of phosphoinositol phosphatase and tensin homologue (PTEN) is dependent on APE1 acetylation (14).Although APE1 heterozygous mice are viable and appear to be normal, APE1 nullizygous mice show early embryonic lethality (37,39,63). We recently showed that APE1 inactivation induced apoptosis in mouse embryo fibroblasts conditionally nullizygous for endogenous APE1, an effect that could be prevented by the ectopic expression of human APE1 (27). Using a complementation assay, we also showed that both the repair activity and acetylation-mediated transcriptional regulatory functions of APE1 are required to prevent the apoptosis of APE1-null mouse embryo fibroblasts. The unexpected essentiality of APE1's regulatory function suggests that APE1 is a coregulator of many critical genes.Resistance to many common anticancer drugs often occurs due to the enhanced expression of ATP-binding cassette (ABC) transporter proteins (6,20). Among the ...

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22–24 (LOD = 6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ∼1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [Pmeta = 5.20×10−14; odds ratio, 95% confidence interval = 0.82 (0.78–0.87)], and two missense variants, rs1990760 (Ala946Thr) [Pmeta = 3.08×10−7; 0.88 (0.84–0.93)] and rs10930046 (Arg460His) [Pdom = 1.16×10−8; 0.70 (0.62–0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.

Objective. Autoimmune diseases often have susceptibility genes in common, indicating similar molecular mechanisms. Increasing evidence suggests that rs6822844 at the IL2-IL21 region is strongly associated with multiple autoimmune diseases in individuals of European descent. This study was undertaken to attempt to replicate the association between rs6822844 and 6 different immune-mediated diseases in nonEuropean populations, and to perform disease-specific and overall meta-analyses using data from previously published studies.Methods. We evaluated case-control associations between rs6822844 and celiac disease (CD) in subjects from Argentina; rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), primary Sjögren's syndrome (SS), and systemic lupus erythematosus (SLE) in subjects from Colombia; and Behçet's disease (BD) in subjects from Turkey. Allele and gene distributions were compared between cases and controls. Meta-analyses were performed using data from the present study and previous studies.Results. We detected significant associations of rs6822844 with SLE (P ‫؍‬ 0.008), type 1 DM (P ‫؍‬ 0.014), RA (P ‫؍‬ 0.019), and primary SS (P ‫؍‬ 0.033) but not with BD (P ‫؍‬ 0.34) or CD (P ‫؍‬ 0.98). We identified little evidence of population differentiation (F ST ‫؍‬ 0.01) within cases and controls from Argentina and Colombia, suggesting that association was not influenced by population substructure. Disease-specific meta-analysis indicated significant association for RA (P meta ‫؍‬ 3.61 ؋ 10 ؊6 ), inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) (P meta ‫؍‬ 3.48 ؋ 10 Conclusion. Our results indicate that there is an association between rs6822844 and multiple autoimmune diseases in non-European populations. Metaanalysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations.Genetic susceptibility plays an important role in autoimmune diseases.