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Biomedical subjects

D Kumari

Publications and source records attributed to D Kumari.

8 recordsLinked to original sources
PubMed2000

Interaction of the transcription factors USF1, USF2, and alpha -Pal/Nrf-1 with the FMR1 promoter. Implications for Fragile X mental retardation syndrome.

Hypermethylation of the FMR1 promoter reduces its transcriptional activity, resulting in the mental retardation and macroorchidism characteristic of Fragile X syndrome. How exactly methylation causes transcriptional silencing is not known but is relevant if current attempts to reactivate the gene are to be successful. Understanding the effect of methylation requires a better understanding of the factors responsible for FMR1 gene expression. To this end we have identified five evolutionarily conserved transcription factor binding sites in this promoter and shown that four of them are important for transcriptional activity in neuronally derived cells. We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs. We also show that methylation abolishes alpha-Pal/Nrf-1 binding to the promoter and affects binding of USF1 and USF2 to a lesser degree. Methylation may therefore inhibit FMR1 transcription not only by recruiting histone deacetylases but also by blocking transcription factor binding. This suggests that for efficient reactivation of the FMR1 promoter, significant demethylation must occur and that current approaches to gene reactivation using histone deacetylase inhibitors alone may therefore have limited effect.

Animals↗
PubMed2000

Detection of deletion in the dystrophin gene of a patient with quadriceps myopathy.

A 43 year old male presented with slowly progressive weakness of limbs and hypertrophy of triceps, brachioradialis and calf muscles for four years. There was thinning of quadriceps muscles in both thighs. Histological study was compatible with Becker muscular dystrophy (BMD). Genomic DNA analysis showed a deletion of the Hind III fragments, spanning exons 45-47. A junction fragment of 11.0 kb was observed along with a deletion of a 3.4 kb PstI fragment containing exon 51 in the patient, and in one of his two sisters. The clinical and laboratory characteristics in this patient are in keeping with what has been described 'quadriceps myopathy' and fall within the phenotypic variants of BMD as has been shown by others.

Adult↗
PubMed1998

Molecular characterisation of Duchenne muscular dystrophy and phenotypic correlation.

Dystrophin gene was analysed in 32 unrelated DMD families (46 subjects: 32 index cases and 14 sibs) for the presence of deletions by mPCR for 27 exons and cDNA probes for the entire gene. Deletions were identified in 32 patients (25 index cases and seven sibs) from 25 families. The concordance between the clinical phenotype and 'reading frame' hypothesis was observed in 24 (75%) cases. Of these, nine patients were wheelchair bound between 8-12 years of age, nine (age range 5-10 years) showed progressive difficulty in walking and six (age range 1.6-4 years) had onset of muscle weakness. One patient (CH), who was wheelchair bound at 12 years, the effect of mutation on the ORF could not be ascertained due to the presence of a junction fragment. Seven patients had inframe deletions of which four were wheelchair bound by the age of 13 years, and three (age range 5-7 years) although, ambulatory had difficulty in walking. There were eight patients who showed no deletion, of which four became wheelchair bound by the age of 12 years, four, though still ambulatory, were unable to run and tired easily. Correlation between phenotype and genotype of these DMD patients demonstrates that genetic studies of lymphocyte DNA may not always reflect the situation in the tissue involved in dystrophin, i.e. muscle. We describe a common dystrophin gene polymorphism in the Indian population with cDNA 11-14 that alters the Hind III restriction sites. Novel RFLPs were observed in 26 patients and their family members. Whether this is a polymorphism or, related to the diseased phenotype needs confirmation.

Adolescent↗
PubMed1994

Effect of retinol on ochratoxin-produced genotoxicity in mice.

Ochratoxin (1 microgram/kg body weight/day), when administered orally daily to albino Swiss mice for 14 continuous days, increased the incidence of abnormalities in mitotic and meiotic metaphase chromosomes, and the gross morphology of the sperm head; the sperm count per unit volume of caput epididymal suspension also decreased. These genotoxic effects were substantially reduced by concurrent oral administration of retinol at double the clinically therapeutic dose. It is possible that the electrophilic metabolites of ochratoxin form adducts with DNA or produce replacement-type mutations. Retinol may achieve its antigenotoxic effect by means of blocks and shunts in the ochratoxin metabolic pathway. Vitamin A-mediated cellular repair and scavenging of the mutagenic radicals can also take place. The vitamin itself has some genotoxic potential.

Animals↗
PubMedDate not supplied

Fragile X syndrome and Friedreich's ataxia: two different paradigms for repeat induced transcript insufficiency.

DNA repeat expansion is the genetic basis for a growing number of neurological disorders. While the largest subset of these diseases results in an increase in the length of a polyglutamine tract in the protein encoded by the affected gene, the most common form of inherited mental retardation, fragile X syndrome, and the most common inherited ataxia, Friedreich's ataxia, are both caused by expansions that are transcribed but not translated. These expansions both decrease expression of the gene in which the expanded repeat is located, but they do so by quite different mechanisms. In fragile X syndrome, CGG. CCG expansion in the 5' untranslated region of the FMR1 gene leads to hypermethylation of the repeats and the adjacent CpG-rich promoter. Methylation prevents the binding of the transcription factor alpha-Pal/NRF-1, and may indirectly affect the binding of other factors via the formation of transcriptionally silent chromatin. In Friedreich's ataxia, GAA. TTC expansion in an intron of the FRDA gene reduces expression by interfering with transcription elongation. The model that best describes the available data is transcription-driven formation of a transient purine. purine. pyrimidine DNA triplex behind an advancing RNA polymerase. This structure lassoes the RNA polymerase that caused it, trapping the enzyme on the template.

DNA Methylation↗