Animal models of inherited metabolic diseases : proceedings of the International Symposium on Animal Models of Inherited Metabolic Disease held in Bethesda, Maryland, October 19-20, 1981 / editors: Robert J. Desnick, Donald F. Patterson, Dante G. Scarpelli.
- International Symposium on Animal Models of Inherited Metabolic Disease (1981 : Bethesda, Md.)
- Date:
- [1982]
Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Credit: Animal models of inherited metabolic diseases : proceedings of the International Symposium on Animal Models of Inherited Metabolic Disease held in Bethesda, Maryland, October 19-20, 1981 / editors: Robert J. Desnick, Donald F. Patterson, Dante G. Scarpelli. Source: Wellcome Collection.
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![Certain mutations (e.g., in the intron, intervening se quence junction or flanking region) may result in the quan titative deficiency, or absence, of normal gene product. Qualitative mutations that alter the structure and function of the normal gene product result from single base substitutions in the exon portion of the gene. From the genetic code, it can be calculated that approximately 70% of single base substitutions in a DNA triplet located in an exon will change that codon to incorporate a different amino acid (missense mutations), about 25% of the sub stitutions will insert the same amino acid (degenerate mutations), and about 5% of substitutions will code for chain termination of the nascent polypeptide sequence (nonsense mutations). Although the rate of gene product synthesis remains relatively normal, missense and nonsense mutations in an exon can alter the kinetic, stability, or other properties of the enzyme, rendering it catalytically inactive or partially active. In the latter case, a muta tion which results in a partially active enzyme permits purification of the residual activity and comparison of its properties with the normal enzyme. In this way, insight into the nature of the enzymatic defect can be obtained. As illustrated in Figure 2, a normal structural gene will be transcribed and translated into a normal gene product with a specific sequence of amino acids that speci fies a unique three-dimensional configuration. This con figuration establishes at least three functional sites on the active enzyme molecule: the substrate binding site, the catalytic or active site, and at least one major anti genic site. There may also be sites for allosteric, co enzyme, and subunit interactions, etc. A single base sub stitution in an exon portion of the gene may alter an enzyme's structure in such a manner as to deleteriously affect one or more of these functional properties. Nonsense or chain-terminating mutations in an exon result in an incompletely synthesized enzyme. If the nonsense mutation occurs early in the enzyme's amino acid sequence, the resultant polypeptide will not have suf ficient structure for catalytic activity or immunologic recognition of its antigenic site(s) [i.e., cross-reacting material (CRM)-negative, Figure 2]. Missense mutations can modify the catalytic, substrate binding, cofactor binding or allosteric sites, resulting in kinetic mutations which](https://iiif.wellcomecollection.org/image/b18027842_0061.JP2/full/800%2C/0/default.jpg)
