Authors: Dr. Berrin Tunca, Department of Medical Biology and Genetics, Faculty of Medicine, Uludag University, Bursa, Turkey
| Abstract:
Base additions or deletions within the coding region of a structural gene can alter the
sequence of codons downstream from these mutation events. These types of alterations are
defined as frame-shift mutations because the reading frame of the normal array of triplets is
shifted.[1] In general; these types of mutations cause the formation of stop codons that
terminate translation. Frame-shift mutations usually have more devastating effects on the
functions of proteins than do many of the base pair substitutions. On the other hand, missense
mutations, which cause a single amino acid (AA) substitution within a protein sequence, may
or may not lead to altered protein function. The severity of a missense mutation depends on
the nature of the substituted amino acid and whether the original amino acid plays an
essential role in the function of the protein.[2] Numerous computational algorithms [SIFT
(Sorting Intolerant From Tolerant; http://blocks.fhcrc.org/sift/SIFT.html), Polyphen
(Polymorphism Phenotyping; http://genetics.bwh.harvard.edu/pph), and Grantham score
difference, Align-GVGD (http://agvgd.iarc.fr)] using genetic, biochemical, and
computational methods have been developed to try to predict which variants cause disease
and which do not.[3] Furthermore, the localizations of missense mutations have an important
role in determining the significance of these alterations. If the missense mutation is localized
at or near the splice site, it can alter the splicing mechanism. In this situation, missense
mutations may have as huge of an effect as frame-shift mutations. The removal of introns
from the primary RNA transcript depends on specific nucleotides at the boundaries of (a) the
end of an exon and the beginning of an intron (5’ splice site) and (b) the end of an intron and
the beginning of the next exon (3’ splice site). The splicing machinery joins nucleotides of a
5’ splice site to those of the next 3’splice site. If the nucleotide sites or neighboring |
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