Fragile X syndrome (FXS), which is the most common form of familial mental retardation, is caused by the expansion of the CGG repeat in the FMR1 gene on the X chromosome. Previous studies have suggested that as compared to other populations, Japanese have a lower prevalence of FXS. In addition, in the normal population, there are no carriers who have the premutation allele. We analyzed a total of 946 normal Japanese (576 males and 370 females) and attempted to estimate the frequency of the FMR1 allele. Within this population, we found that 1,155 alleles were in the normal range (less than 40 CGG repeats) and had a modal number of 27 repeats (35.75%). No carriers with premutations (55-200 CGG repeats) were observed in this normal population. We also identified six intermediate-sized alleles (40-54 CGG repeats), with a reported incidence of 1 in 103 males and 1 in 324 females. However, this allele frequency was different from that previously reported for the Japanese population. Since data from previous studies has suggested that FXS might possibly be associated with the genetic mechanism of autism, we also analyzed the length of the CGG repeats in 109 autistic patients. In all cases the CGG repeat numbers were within the normal range (16-36 repeats) and no individuals presented with expanded premutation or intermediate alleles. This finding indicates that the length of the CGG repeat within the FMR1 is unlikely to be responsible for autism in Japanese.

It has been proven that the fatty acids of esterified phospholipids in the cell membrane play an important role in membrane fluidity. Our previous in vitro experiment indicated that the impairment of erythrocyte membrane fluidity might be largely because of the change in fatty acids. The aim of this study is to clarify changes of cell membrane fatty acids in more detail in relation to various stages and pathology of alcoholic liver disease. For the analysis, erythrocyte membranes were exploited on the assumption that their fatty acid compositions may be similar to those of other organs. In alcoholic liver disease, unsaturated fatty acids in the erythrocyte membrane decreased and saturated fatty acids increased. Consequently, the unsaturated fatty acid/saturated fatty acid ratio decreased significantly. When fractions of saturated fatty acids were studied, myristic acid (C14:0) increased markedly in the alcoholic group, and the increase was striking particularly in the cases of alcoholic hepatitis concurrently with hemolysis. Palmitic acid (C16:0) also tended to increase in the alcoholic liver disease group. A longer chain saturated fatty acid, stearic acid (C18:0), showed a moderate but significant increase in the alcoholic fatty liver and hepatic fibrosis group, but it decreased significantly in the alcoholic liver cirrhosis, as with the finding in viral liver cirrhosis. As with unsaturated fatty acids, linoleic acid (C18:2), arachidonic acid (C20:4), and eicosapentanoic acid (C20:5) decreased significantly. The arachidonic acid/linoleic acid ratio, which indicates microsomal elongation activity of liver cells, was found to be broadly distributed. No significant change was found in each group of alcoholic liver disease. However, the cases showing a decrease in this ratio had severe hepatic dysfunction concurrently. Thrombogenic Index, serving as an indicator for fatty acids in food, and that is concerned with formation of thrombus, was studied, using fatty acid fractions of the erythrocyte membrane. The index was significantly increased in alcoholic liver disease. It was suggested that the chronic alcohol intake and the resultant liver diseases might enhance the abnormality of the membrane fatty acid composition. These changes may affect cell membrane fluidity and eventually metabolic functions of the cell.

We studied the relationship between changes in platelet aggregability and platelet membrane lipid in alcoholic liver disease. The maximal rate of ADP‐induced platelet aggregation was significantly increased in the alcoholic liver disease group than in the control group. No significant difference was observed in the maximal rate of collagen‐induced platelet aggregation. However, a lag time required for the start of platelet aggregation was significantly shortened in the alcoholic liver disease group, indicating increased platelet aggregability. Results of the platelet aggregation test suggested that alcoholic liver disease patients have their platelet aggregation affected by the abnormality of prostaglandin metabolism. The alcoholic liver disease group was further divided into two subgroups: the hyperaggregation group and the unchanged aggregation group. Both free cholesterol and phospholipid in the platelet membrane were significantly increased in the alcoholic liver disease group. In phospholipid compositions, phosphatidylserine plus phosphatidylinositol were significantly decreased in the alcoholic liver disease group, whereas a significant decrease in phosphatidylserine plus phosphatidylinositol was observed in the hyperaggregation group of alcoholic liver disease. Analysis of fatty acid compositions of platelet membrane showed significantly decreased palmitic acid in the alcoholic group. There was no significant change of arachidonic acid, which directly affects platelet aggregation. Eicosapentaenoic acid significantly decreased in the alcoholic liver disease group, but there was no difference in docosahexaenoic acid. Meanwhile, the thrombogenic index, calculated from the fatty acids of platelet membrane, showed no difference between the alcoholic liver disease group and the control group. However, the thrombogenic index was significantly increased in the hyperaggregation group than in the unchanged aggregation group. These data suggested that platelet aggregation is affected by not only a change in arachidonic acid, but also changes in fatty acid compositions of the platelet membrane.

To investigate the role of human aldose reductase (bAR) in the pathogenesis of diabetic complications, we generated transgenic mice carrying hAR cDNA driven by the murine MHC class I molecule promoter (hAR-Tg). Northern and Western blot analyses and immunoassay of hAR revealed that both hAR mRNA and the protein were expressed in all tissues tested. Thrombosis in renal vessels and fibrinous deposits in Bowman's capsule were observed in 6-week-old hAR-Tg mice fed a normal diet. Ingestion of a 30 % glucose diet for 5 days caused sorbitol concentrations in the liver, kidney, and muscle of hAR-Tg mice to be elevated significantly. Seven-week-old hAR-Tg mice fed a 20 % galactose diet for 7 days developed cataracts and occlusion of the retinochoroidal vessels, in addition to pathological changes in the kidney. Despite an elevated aldose reductase level in hAR-Tg mice and their intake of an aldose diet, no histopathological changes were found in other tissues, including the brain, lungs, heart, thymus, spleen, intestine, liver, muscle, spinal cord, or sciatic nerve. Results suggest that target organs of diabetic complications, such as the kidney, lens, and retina are sensitive to damage associated with a high level of AR expression, but other organs are not; the susceptibility of each organ to diabetic complications is determined by not only hAR but also other factors. [Diabetologia (1995) 38: 255-261]

AimsKrüppel-like factor 11 (KLF11) is a transcriptional factor of the zinc finger domain family that regulates the expression of insulin. In North European populations, its common functional variant Q62R (rs35927125) is a strong genetic factor for Type 2 diabetes (P = 0.00033, odds ratio for G allele = 1.29, 95% CI 1.12–1.49). We examined the contribution of KLF11 variants to the susceptibility to Type 2 diabetes in a Japanese population.MethodsBy re-sequencing Japanese individuals (n = 24, partly 96), we screened all four exons, exon/intron boundaries and flanking regions of KLF11. Verified single nucleotide polymorphisms (SNPs) were genotyped in 731 initial samples (369 control and 362 case subjects). Subsequently, we tested for association in 1087 samples (524 control and 563 case subjects), which were collected in different districts of Japan from the initial samples.ResultsWe identified eight variants, including a novel A/C variant on intron 3, but no mis-sense mutations. In an association study, we failed to find any significant result of SNPs (minor allele frequency 8.2–46.2%) after correcting for multiple testing. Similarly, no haplotypes were associated with Type 2 diabetes. It is notable that the G allele in rs35927125 was completely absent in 1818 Japanese individuals.ConclusionsGenetic variants in KLF11 are unlikely to have a major effect of Type 2 diabetes in the Japanese population, although they were significantly associated in North European populations. These observations might help to determine the role of KLF11 variants in Type 2 diabetes in different populations.