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ABSTRACT: 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.
Brain & development 03/2009; 32(2):110-4. · 1.74 Impact Factor
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ABSTRACT: Glioma includes astrocytoma, oligodendroglioma, ependymoma and glioblastoma. We previously reported the epigenetic silencing of paternally expressed gene 3 (PEG3) in glioma cell lines. In this study, we investigated methylation of an exonic CpG island in the promoter region and the expression of PEG3 gene in 20 glioma and 5 non-tumor tissue samples. We found wide variations in the methylation level. Hypomethylaiton and hypermethylation was found in 3 and 4 glioma tissue samples, respectively. Monoallelic expression, which is an evidence of an imprinted gene, was maintained in eight out of nine informative cases which have T/C polymorphisms in PEG3. The lower gene expression, which suggested epigenetic silencing of PEG3, was confirmed statistically in glioblastoma using quantitative reverse-transcription polymerase chain reaction. Interestingly, we found higher expression of PEG3 in two out of three oligodendrogliomas. A negative correlation between the methylation level and gene expression was shown by regression analysis. These results suggest that the abnormal regulation of PEG3 is associated with several glioma subtypes and that it plays an important role in tumorigenesis.
Proceedings of the Japan Academy Ser B Physical and Biological Sciences 02/2009; 85(4):157-65. · 2.77 Impact Factor
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ABSTRACT: G(M1)-gangliosidosis is an autosomal recessive lysosomal lipid storage disorder, caused by mutations of the lysosomal beta-galactosidase (beta-gal) and results in the accumulation of G(M1). The underlying mechanisms of neurodegeneration are poorly understood. Here we demonstrate increased autophagy in beta-gal-deficient (beta-gal(-/-)) mouse brains as evidenced by elevation of LC3-II and beclin-1 levels. Activation of autophagy in the beta-gal(-/-) brain was found to be accompanied with enhanced Akt-mTOR and Erk signaling. In addition, the mitochondrial cytochrome c oxidase activity was significantly decreased in brains and cultured astrocytes from beta-gal(-/-) mouse. Mitochondria isolated from beta-gal(-/-) astrocytes were morphologically abnormal and had a decreased membrane potential. These cells were more sensitive to oxidative stress than wild type cells and this sensitivity was suppressed by ATP, an autophagy inhibitor 3-methyladenine and a pan-caspase inhibitor z-VAD-fmk. These results suggest activation of autophagy leading to mitochondrial dysfunction in the brain of G(M1)-gangliosidosis.
Biochemical and Biophysical Research Communications 04/2008; 367(3):616-22. · 2.48 Impact Factor
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ABSTRACT: The human paternally expressed gene 3 (PEG3) on chromosome 19q13.4 is one of the candidate tumor suppressor genes for glioma. We have previously reported that the epigenetic silencing of PEG3 expression in glioma cell lines is dependent on aberrant DNA methylation of an exonic CpG island. Here, we have identified three expressed sequence tags (ESTs), H80201, H78825 and AW197312, that exhibit paternal allele-specific expression, using human monochromosomal hybrids containing the paternal or maternal origin of PEG3 locus. The EST H80201 was shown to be expressed only from the paternal allele in normal human lymphoblasts by utilizing a single nucleotide polymorphism (SNP). Monoallelic expression of EST H80201 was also detected in non-tumor adult human brain tissues of gliomas. These ESTs were located directly adjacent to PEG3 in a head-to-head orientation. We have named this new transcript, imprinted transcript 1, which is located upstream but oppositely oriented to PEG3 (ITUP1). The ITUP1 showed a similar expression profile with PEG3 in glioma cell lines. Bisulfite genomic sequencing and reverse transcription (RT)-PCR analysis indicated that hypermethylation of the promoter region correlated with the absence of these transcripts. This suggests that ITUP1 and PEG3 are coordinately regulated, and that downregulation of the both genes may be important in the development of glioma.
DNA Research 03/2004; 11(1):37-49. · 5.16 Impact Factor
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ABSTRACT: GM1-gangliosidosis is an autosomal recessive lysosomal lipid storage disorder, caused by mutations of the lysosomal β-galactosidase (β-gal) and results in the accumulation of GM1. The underlying mechanisms of neurodegeneration are poorly understood. Here we demonstrate increased autophagy in β-gal-deficient (β-gal−/−) mouse brains as evidenced by elevation of LC3-II and beclin-1 levels. Activation of autophagy in the β-gal−/− brain was found to be accompanied with enhanced Akt–mTOR and Erk signaling. In addition, the mitochondrial cytochrome c oxidase activity was significantly decreased in brains and cultured astrocytes from β-gal−/− mouse. Mitochondria isolated from β-gal−/− astrocytes were morphologically abnormal and had a decreased membrane potential. These cells were more sensitive to oxidative stress than wild type cells and this sensitivity was suppressed by ATP, an autophagy inhibitor 3-methyladenine and a pan-caspase inhibitor z-VAD-fmk. These results suggest activation of autophagy leading to mitochondrial dysfunction in the brain of GM1-gangliosidosis.
Biochemical and Biophysical Research Communications.
