An SNP in the trinucleotide repeat region of the TNRC6A gene maps to a major TNGW1 autoepitope in patients with autoantibodies to GW182.

GW/P bodies contain two TNRC6A protein isoforms (GW182 and TNGW1) that function as translational repressors of mRNA through Ago2-mediated RNA silencing. Autoantibodies to GW/P body components GW182, Ge-1 and Ago2 have previously been correlated with clinical autoimmune diseases including neurological disease, Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis and primary biliary cirrhosis. No studies were published to date examining if patients with autoantibodies directed against GW/P bodies contain autoantibodies to the trinucleotide repeat (TNR) region of TNGW1, which differs from GW182 only by the addition of an N-terminal QP-rich 253 amino acid sequence. Our data show that 85.7% of GW/P body positive plasma contain autoantibodies to various epitopes in the TNR region of TNGW1. Given the association of neurological diseases with autoantibodies directed to the TNR region on exon 5 of TNRC6A, this study examined whether there were TNR expansions as described in other neurological diseases and/or mutations in the nucleotide sequence of the CAG/CCA/G-rich region in seven anti-GW/P body positive patients, six control and eight breast cancer patients. Although a TNR expansion was not identified, 28.6% of patients containing autoantibodies to the TNR of TNGW1 were shown to have a single nucleotide polymorphism (SNP) at c.344C > A in the CAG/CCA/G-rich region of TNRC6A, which when translated, would produce a protein variant of p.Pro115Gln. The amino acid change may alter the structure of TNGW1 and/or perturb its miRNA regulatory function although this has not been examined experimentally. A putative change in protein structure may lead to a loss of tolerance to the TNGW1 protein or result in a "neo-antigen" in patients containing the specific TNRC6A SNPs. Further studies of a larger cohort of GW/P body positive patients and structure-function relationships of the variant TNRC6A are required to fully understand the role that such SNPs play in GW/P body autoantibody production and/or pathogenesis of related autoimmune diseases.

The FMR1 gene as regulator of ovarian recruitment and ovarian reserve.

The fragile X mental retardation 1 (FMR1) gene is primarily associated with neuro/psychiatric risks. Recent evidence suggests that the gene also exerts controlling functions on follicle recruitment and ovarian reserve (OR). We performed unrestricted Medline and PubMed searches of the medical literature independently under search terms, FMR1 gene, fragile X gene, and in association with premature ovarian aging, primary ovarian insufficiency, occult primary insufficiency, premature ovarian failure, premature menopause, ovarian reserve (OR), diminished ovarian reserve, follicle recruitment and ovarian aging. We also used web-based resources in regards to the FMR1 gene and reviewed additional citations from reviewed publications. Recently published data strongly suggest an independent function of the FMR1 gene on ovaries. This function appears distinct from the gene's neuro/psychiatric effects, associated with a different, and specific, triple nucleotide (CGG) repeat range and characterized by specific genotypes. Ovarian function in all races/ethnicities appears defined by a normal range of 26 to 34 CGG repeats (mean 30), including the reported distribution peak of 29 to 30 repeats in humans and maximal gene translation, reported at 30 repeats. Genotypes, defined by 2 normal count alleles (normal) demonstrate different OR aging patterns from women with 1 (heterozygous) or both alleles outside of range (homozygous). Heterozygous and homozygous genotypes recruit fewer follicles at younger ages, thus preserving OR into advanced age. These observations suggest a direct FMR1 effect on follicular recruitment and OR and, therefore, on women's fecundity.

[Thermodynamic characterization of di-, tri-, and tetranucleotide loci in parthenogenetic lizards Darevskia unisexualis].

Allelic polymorphism of three microsatellite loci from the genome of parthenogenetic lizard Darevskia unisexualis was characterized using analysis of free energy (Gibbs energy) of the DNA/DNA duplex formation within the stepwise mutational model. It was demonstrated that the number of microsatellite cluster monomericic units would change to decrease the mean free energy of the locus. In addition, based on the analysis of nucleotide composition, the GC content of each locus was evaluated, and belonging of the loci examined to certain isochore families was suggested.

MICA A8: a new allele within MHC class I chain-related A transmembrane region with eight GCT repeats.

Analysis of the MICA gene revealed a trinucleotide repeat (GCT) microsatellite polymorphism within the transmembrane region. So far, seven alleles of the exon 5 of the MICA gene, which consist of 4, 5, 6, 7, 9, and 10 repetitions of GCT or five repetitions of GCT with an additional nucleotide insertion (GGCT), have been identified. These alleles have been accordingly named A4, A5, A6, A7, A9, A10, and A5.1, and the sizes are, respectively, 179 bp, 182 bp, 186 bp, 189 bp, 194 bp, 197 bp, and 185 bp. We analyzed 1100 Italian subjects for MICA exon 5 microsatellite polymorphism. A new peak corresponding to 191-bp size was observed in one individual, and we confirmed the presence of new polymorphism in exon 5 by sequencing, which consisted of eight GCT repeats. We named this allele, as a current nomenclature, MICA8.

Slipped (CTG).(CAG) repeats of the myotonic dystrophy locus: surface probing with anti-DNA antibodies.

At least 15 human diseases have been associated with the length-dependent expansion of gene-specific (CTG).(CAG) repeats, including myotonic dystrophy (DM1) and spinocerebellar ataxia type 1 (SCA1). Repeat expansion is likely to involve unusual DNA structures. We have structurally characterized such DNA, with (CTG)(n).(CAG)(n) repeats of varying length (n=17-79), by high-resolution gel electrophoresis, and have probed their surfaces with anti-DNA antibodies of known specificities. We prepared homoduplex S-DNAs, which are (CTG)x.(CAG)y where x=y, and heteroduplex SI-DNAs, which are hybrids where x>y or x

Polymorphism of transmembrane region of MICA gene and Kawasaki disease.

Kawasaki disease is a febrile disease of children complicated with vasculitis of the coronary arteries and potential aneurysm formation. It has been recognized worldwide and appears to be increasing in frequency. Studies have found that Kawasaki disease is associated with major histocompatibility complex (MHC) class I B antigens. The MHC-class-I-chain-related gene A (MICA) is located near HLA-B. It has a triplet repeat microsatellite polymorphism in the transmembrane region. We investigated the microsatellite polymorphism in children with Kawasaki disease and controls. Seventy children (46 boys), age at diagnosis 1.68 +/- 1.69 years, with Kawasaki who were treated with aspirin as well as intravenous gamma-globulin were enrolled. Control subjects consisted of 154 children (87 boys), age 2.81 +/- 2.12 years. Phenotype frequency of allele A4 in patients with aneurysm formation was significantly lower than in patients without aneurysms [relative risk (RR) = 0.06, 95% confidence interval (CI) = 0.01-0.48, p = 0.00469, pc = 0.0232] and showed a similar tendency when compared with controls. Gene frequency of allele A4 was also significantly lower in patients who developed aneurysms than in patients who did not (RR = 0.07, 95% CI = 0.01-0.57, p = 0.0057, pc = 0.0282). Gene frequency of allele A5 showed a tendency to be higher in patients who developed aneurysms than in controls (RR = 2.35, 95% CI = 0.98-5.63, p = 0.0486, pc = 0. 220). Allele A5.1 tended to be negatively associated with Kawasaki disease (RR = 0.57, 95% CI = 0.35-0.93, p = 0.022, pc = 0.105). Our study showed that allele A4 was negatively associated with coronary aneurysm formation in Kawasaki disease. This suggests that allele A4 protects the children with Kawasaki disease from developing coronary aneurysms after aspirin and gamma globulin therapy.

New polymorphic microsatellite markers in the human MHC class II region.

The human major histocompatibility complex (MHC) class II region spans approximately 1.1 Mb and presently contains over 30 functional genes Susceptibility loci to numerous diseases, mainly of autoimmune nature are known to map to the this region, as assessed by associations with particular HLA class II alleles. However, it has been difficult to precisely localize these susceptibility loci to a single gene, for example DQB1 or DRB1, due to the tight linkage disequilibrium observed in the HLA class II region. To facilitate disease mapping within this region, we have analyzed 2 to approximately 5 bases short tandem repeats (microsatellites) in this same region. A total of 494 microsatellites were identified from the genomic sequence of the HLA class II region. These consist of 158 di-, 65 tri-, 163 tetra-, and 108 pent-nucleotide repeats, out of which four were located within the coding sequence of expressed genes (Daxx, BING1, RXRB and COL11A2). Twenty-two repeats were selected as polymorphic markers due to their high (average) number of alleles (8.9) as well as their high polymorphic content value (PIC) (0.58). These novel polymorphic microsatellites will provide useful genetic markers in HLA-related research, such as genetic mapping of HLA class II-associated diseases, transplantation matching, population genetics, identification of recombination hot spots as well as linkage disequilibrium studies.

MICA 5.1 allele is a susceptibility marker for psoriasis in the Korean population.

In order to investigate the possibility that the MICA gene is involved in the pathogenesis of psoriasis, microsatellite polymorphism in the transmembrane region of MICA was studied in 138 Korean patients with psoriasis and compared with 126 healthy controls. The MICA 5.1 microsatellite allele, consisting of 5.1 repetitions of GCT/AGC, showed significantly higher frequencies in all patients and in patients with type I psoriasis than in the controls. HLA-A30-B13-Cw*0602-MICA 5.1 and A1-B37-Cw*0602-MICA 5.1 were found to be an extended haplotype associated with psoriasis. Our results suggest that the MICA 5.1 allele might be a genetic marker related to the early onset of psoriasis and play a secondary role to the HLA-Cw*0602 gene or an unknown causative gene closely linked to HLA-Cw*0602 in the genetic susceptibility to psoriasis.