Nucleotide molecular defects

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

Although the molecular defect of XPV is very different from that of the other XP patients (XPA, XPB, XPC, XPD, XPE, XPF, and XPG), who are deficient in nucleotide excision repair, the clinical manifestations of the diseases are quite similar. This is not surprising because the defect in either Polq or nucleotide excision repair results in a common problem genomic overload of TT dimers and perhaps other CPDs for error-prone translesion synthesis by other bypass polymerases during replication. The result is predictable elevated cytotoxicity and mutagenesis induced by the UV component of the sunlight, which constitute the cellular bases of XP diseases. 

The molecular defect has recently been linked [7] to a single base substitution, an A—transversion, in the penultimate 3 nucleotide of the third intron of the Apo E gene. This leads to a loss of the correct 3 splice site, thus giving rise to two abnormally spliced mRNA forms. The smaUer form contains 53 nucleotides and the larger one, the entire third intron of the gene. Since both mRNA species contain chain termination codons within the intronic sequence, only short Apo E peptides not detectable by standard gel electrophoretic techniques are produced. Apo E deficiency is, therefore, the result of a molecular error which gives rise to shorter, nonfunctional forms of Apo E. In contrast to Apo B, where the mechanism is posttranslational, here it is clearly pretranslational. 

DNA repair, some associated with skin cancer19. Such disorders result from defects in nucleotide excision repair and are all genetically complex, with involvement of multiple genes. Here again, the Xiphophorus model offers a potential means of unraveling each of the many steps involved in these complex molecular events that underpin multifactorial phenotypes. 

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