Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D02011 (FAD)
 5,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alzheimer disease (AD) is a devastating neurodegenerative disease leading to global dementia. The familial form (FAD) has been linked to markers on chromosome 21 in some families, most tightly to the loci D21S16 and D21S13 located close to the centromere of the long arm. In other families the FAD mutation has been excluded from the more telomeric D21S1/S11 region, but not from the centromeric region of chromosome 21. We identified two new restriction fragment length polymorphisms (RFLPs) for the locus D21S13 and have used these RFLPs for the analysis of one of the largest known early-onset FAD pedigrees. We calculated pairwise and multipoint lod scores for the loci D21S13, D21S110, and D21S11. Linkage to this region of chromosome 21 was excluded with maximum negative lod scores of -6.4 at D21S13 and D21S110. Thus, it is unlikely that the FAD mutation in this family is located in the region that has shown linkage in other FAD pedigrees. This result provides evidence for genetic heterogeneity of early-onset FAD or a location of FAD centromeric to D21S13.
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PMID:Exclusion of linkage to the pericentromeric region of chromosome 21 in the Canadian pedigree with familial Alzheimer disease. 167

A detailed genetic linkage map of human chromosome 21 will allow the rapid regional assignment of future genes and DNA markers to this autosome. It will also facilitate the precise mapping of the genes responsible for the DS phenotype and the defect causing FAD. This map can also be used to implicate genes involved with specific features of the DS phenotype by permitting the delineation of finite regions of chromosome 21 which are duplicated in patients with partial trisomy 21, and who manifest select symptoms of the DS phenotype. In the case of FAD, most pedigrees are not ideally structured for genetic linkage analysis since affected individuals die relatively soon (6-8 years) after the onset of symptoms. By first establishing the genetic relationships of DNA markers in the vicinity of the FAD defect, multipoint analyses of these markers can then be performed in FAD families. Multipoint analysis carries a greater probability of identifying markers flanking the FAD locus thereby providing landmarks for cloning attempts aimed at isolating and characterizing the FAD gene defect. We have confirmed our initial findings of a dramatically increased rate of recombination at the telomere in both females and males, and significantly higher recombination in females in the pericentromeric region between D21S1/S11 and D21S13/S16. By comparing patterns of recombination in specific regions of chromosome 21 with regard to both parental sex and age, we have identified a statistically significant downward trend in in the frequency of crossovers in the most telomeric portion chromosome 21 with increasing maternal age. A less significant decrease in recombination with increasing maternal age was observed in the sub-centromeric region of the chromosome where recombination in females is overall higher than in males. Future confirmation of these results in combination with investigations aimed at deciphering the role played by recombination in promoting normal segregation during meiosis should help to elucidate the potential relevance of these findings to the etiological basis of nondisjunction.
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PMID:Detailed genetic linkage map of human chromosome 21: patterns of recombination according to age and sex. 224 6

The pig and human dihydropyrimidine dehydrogenase (DPD) cDNAs were cloned and sequenced. The pig enzyme, expressed in Escherichia coli, catalyzed the reduction of uracil, thymine, and 5-fluorouracil with kinetics approximating those published for the enzyme purified from mammalian liver. DPD could be expressed in significant quantities only when uracil was added to the bacterial growth medium. The pig and human enzymes contained 1025 amino acids and calculated M(r) = 111,416 and 111,398, respectively. Conserved domains corresponding to a possible NADPH binding site and FAD binding site were found in the NH2-terminal half of the proteins and two motifs of putative [4Fe-4S] binding sites were found near to the carboxyl terminus of the enzyme. The latter corresponds to the labile COOH-terminal fragment previously shown to contain the iron sulfur centers. A sequence encompassing a peptide corresponding to the uracil binding site was found between the NADPH/FAD-containing NH2-terminal portion of the protein and the iron-sulfur binding sites near to the COOH terminus. Thus, the DPD appears to be derived from at least three distinct domains. The DPYD gene was localized to the centromeric region of human chromosome 1 between 1p22 and q21.
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PMID:cDNA cloning and chromosome mapping of human dihydropyrimidine dehydrogenase, an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria. 808 24