Candidate genes for male factor infertility--validation.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
Mariko Taniguchi
Publications and source records attributed to Mariko Taniguchi.
Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in alpha-dystroglycanopathies.
Recent studies have revealed an association between post-translational modification of alpha-dystroglycan (alpha-DG) and certain congenital muscular dystrophies known as secondary alpha-dystroglycanopathies (alpha-DGpathies). Fukuyama-type congenital muscular dystrophy (FCMD) is classified as a secondary alpha-DGpathy because the responsible gene, fukutin, is a putative glycosyltransferase for alpha-DG. To investigate the pathophysiology of secondary alpha-DGpathies, we profiled gene expression in skeletal muscle from FCMD patients. cDNA microarray analysis and quantitative real-time polymerase chain reaction showed that expression of developmentally regulated genes, including myosin heavy chain (MYH) and myogenic transcription factors (MRF4, myogenin and MyoD), in FCMD muscle fibers is inconsistent with dystrophy and active muscle regeneration, instead more of implicating maturational arrest. FCMD skeletal muscle contained mainly immature type 2C fibers positive for immature-type MYH. These characteristics are distinct from Duchenne muscular dystrophy, suggesting that another mechanism in addition to dystrophy accounts for the FCMD skeletal muscle lesion. Immunohistochemical analysis revealed morphologically aberrant neuromuscular junctions (NMJs) lacking MRF4 co-localization. Hypoglycosylated alpha-DG indicated a lack of aggregation, and acetylcholine receptor (AChR) clustering was compromised in FCMD and the myodystrophy mouse, another model of secondary alpha-DGpathy. Electron microscopy showed aberrant NMJs and neural terminals, as well as myotubes with maturational defects. Functional analysis of NMJs of alpha-DGpathy showed decreased miniature endplate potential and higher sensitivities to d-Tubocurarine, suggesting aberrant or collapsed formation of NMJs. Because alpha-DG aggregation and subsequent clustering of AChR are crucial for NMJ formation, hypoglycosylation of alpha-DG results in aberrant NMJ formation and delayed muscle terminal maturation in secondary alpha-DGpathies. Although severe necrotic degeneration or wasting of skeletal muscle fibers is the main cause of congenital muscular dystrophies, maturational delay of muscle fibers also underlies the etiology of secondary alpha-DGpathies.
Animals↗
Genetic variation affects de novo translocation frequency.
Translocation is one of the most frequently occurring human chromosomal aberrations. The constitutional t(11;22)(q23;q11), which is the only known recurrent non-Robertsonian translocation, represents a good model for studying translocations in humans. Here we demonstrate polymorphisms of the palindromic sequence at the t(11;22) breakpoint that affect the frequency of de novo translocations in sperm from normal males. A typical allele consists of a perfect palindrome, producing ~10-5 de novo t(11;22) translocations. Alleles with an asymmetric center do not form the t(11;22). Our data show the importance of genome sequence on chromosomal rearrangements, a class of human mutation that is thought to be random.
AT Rich Sequence↗
Expression profiling of muscles from Fukuyama-type congenital muscular dystrophy and laminin-alpha 2 deficient congenital muscular dystrophy; is congenital muscular dystrophy a primary fibrotic disease?
Fukuyama-type congenital muscular dystrophy (FCMD) and laminin-alpha2 deficient congenital muscular dystrophy (MDC1A) are congenital muscular dystrophies (CMDs) and they both are categorized into the same clinical entity of muscular dystrophy as Duchenne muscular dystrophy (DMD). All three disorders share a common etiologic defect in the dystrophin-glycoprotein complex, which connects muscle structural proteins with the extracellular basement membrane. To investigate the pathophysiology of these CMDs, we generated microarray gene expression profiles of skeletal muscle from patients in various clinical stages. Despite diverse pathological changes, the correlation coefficient of overall gene expression among these samples was considerably high. We performed a multi-dimensional statistical analysis, the Distillation, to extract determinant genes that distinguish CMD muscle from normal controls. Up-regulated genes were primarily extracellular matrix (ECM) components, whereas down-regulated genes included structural components of mature muscle. These observations reflect active interstitial fibrosis with less active regeneration of muscle cell components in the CMDs, characteristics that are clearly distinct from those of DMD. Although the severity of fibrosis varied among the specimens tested, ECM gene expression was consistently high without substantial changes through the clinical course. Further, in situ hybridization showed more prominent ECM gene expression on muscle cells than on interstitial tissue cells, suggesting that ECM components are induced by regeneration process rather than by 'dystrophy.' These data imply that the etiology of FCMD and MDC1A differs from that of the chronic phase of classical muscular dystrophy, and the major pathophysiologic change in CMDs might instead result from primary active fibrosis.
Child↗
Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells.
OBJECTIVE: To examine the promoter activity and protein expression of the death receptor 3 gene DR3, a member of the apoptosis-inducing Fas gene family, with particular reference to the methylation status of its promoter region in rheumatoid arthritis (RA). METHODS: Genomic DNA was prepared from peripheral blood mononuclear cells obtained from healthy individuals and from patients with RA and synovial cells obtained from patients with RA and osteoarthritis. The methylation status of the DR3 promoter was analyzed by bisulfite genomic sequencing and methylation-specific polymerase chain reaction techniques. Gene promoter activity and protein expression were examined using the luciferase reporter and Western blotting techniques. RESULTS: The promoter region of the DR3 gene contained many CpG motifs, including one CpG island that was specifically hypermethylated in synovial cells from patients with RA. Promoter assays showed that the promoter CpG island was essential for the transactivation of the DR3 gene and that forced hypermethylation of the CpG island with the bacterial methylase Sss I in vitro resulted in inhibition of the DR3 gene expression. Furthermore, the expression of DR-3 protein was down-modulated in association with methylation of the promoter CpG island in RA synovial cells. CONCLUSION: The CpG island in the DR3 gene promoter was specifically methylated to down-modulate the expression of DR-3 protein in rheumatoid synovial cells, which may provide resistance to apoptosis in RA synovial cells.
Adult↗
Analysis of gene-expression profiles by oligonucleotide microarray in children with influenza.
In order to clarify the mechanism of the host response to influenza virus, gene-expression profiles of peripheral blood obtained from paediatric patients with influenza were investigated by oligonucleotide microarray. In the acute phase of influenza, 200 genes were upregulated and 20 genes were downregulated compared with their expression in the convalescent phase. Interferon-regulated genes, such as interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) and vipirin, were strongly upregulated in the acute phase. Gene ontology analysis showed that immune response genes were highly overrepresented among the upregulated genes. Gene-expression profiles of influenza patients with and without febrile convulsion were also studied. In patients with febrile convulsion, 22 genes were upregulated and five were downregulated compared with their expression in patients without febrile convulsion. These results should help to clarify the pathogenesis of influenza and its neurological complications.
Acute Disease↗
Cruciform DNA structure underlies the etiology for palindrome-mediated human chromosomal translocations.
There is accumulating evidence to suggest that palindromic AT-rich repeats (PATRRs) represent hot spots of double-strand breakage that lead to recurrent chromosomal translocations in humans. As a mechanism for such rearrangements, we proposed that the PATRR forms a cruciform structure that is the source of genomic instability. To test this hypothesis, we have investigated the tertiary structure of a cloned PATRR. We have observed that a plasmid containing this PATRR undergoes a conformational change, causing temperature-dependent mobility changes upon agarose gel electrophoresis. The mobility shift is observed in physiologic salt concentrations and is most prominent when the plasmid DNA is incubated at room temperature prior to electrophoresis. Analysis using two-dimensional gel electrophoresis indicates that the mobility shift results from the formation of a cruciform structure. S1 nuclease and T7 endonuclease both cut the plasmid into a linear form, also suggesting cruciform formation. Furthermore, anti-cruciform DNA antibody reduces the electrophoretic mobility of the PATRR-containing fragment. Finally, we have directly visualized cruciform extrusions from the plasmid DNA with the size expected of hairpin arms using atomic force microscopy. Our data imply that for human chromosomes, translocation susceptibility is mediated by PATRRs and likely results from their unstable conformation.
Animals↗
Fukuyama-type congenital muscular dystrophy (FCMD) and alpha-dystroglycanopathy.
Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain (MEB) disease are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. Through positional cloning, we identified the gene for FCMD and MEB, which encodes the fukutin protein and the protein O-linked mannose beta1, 2-N-acetylglucosaminy ltransferase (POMGnT1), respectively. Recent studies have revealed that posttranslational modification of alpha-dystroglycan is associated with these congenital muscular dystrophies with brain malformations. In this review Fukuyama-type congenital muscular dystrophy (FCMD), other CMDs with brain malformations, and their relation with alpha-dystroglycan are discussed.
Animals↗
Basement membrane fragility underlies embryonic lethality in fukutin-null mice.
Fukuyama-type congenital muscular dystrophy (FCMD), associated with brain malformation due to defects in neuronal migration, is caused by mutations in fukutin. Several lines of evidence suggest that the fukutin protein plays a pivotal role in synthesis of O-mannosyl sugar moieties of alpha-dystroglycan, a cell surface laminin receptor. Here, through targeted disruption of the orthologous mouse fukutin gene, we show that the fukutin protein is essential, as homozygous-null embryos die by E9.5 of gestation. Fukutin-null embryos show phenotypic diversity, features of which include growth retardation, folding of the egg cylinder, leakage of maternal red blood cells into the yolk sac cavity, and an increased number of apoptotic cells in the ectoderm. Loss of immunoreactivity against sugar moieties in alpha-dystroglycan suggests a reduced laminin-binding capacity. Ultrastructural analysis shows thin and breached basement membranes (BMs). BM fragility may underlie all of these abnormal phenotypes, and maintenance of BM function may require fukutin-mediated glycosylation of alpha-dystroglycan early in embryonic development.
Animals↗