Biology Reference
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tively, if the addition or deletion is not in multiples of three, a frameshift
occurs, since the codon reading frame is now altered. Frameshifts result in
the addition of incorrect amino acids to the elongating protein. Ultimately,
frameshifts will terminate at a stop codon farther downstream. Because of
the addition of incorrect amino acids, in some cases, the mutated protein is
recognized by the cell as nonfunctional. This may be because the protein
is not targeted to its correct location within the cell, or because the protein
is not exhibiting the correct enzymatic activity. In these cases, the mutated
protein is often destabilized and is degraded by the cell.
In addition to DNA mutations that directly alter protein sequence, point
mutations, insertions and deletions can also affect sequences essential for
the initiation of transcription and translation. Ultimately, these types of
mutations have the same result as mutations in the coding regions, namely
that the encoded protein is not correctly expressed.
Silent mutations, or variants, occur when a substitution in a nucleotide
occurs without altering the amino acid. Single-nucleotide polymorphisms
(SNPs), the most frequent type of variation in the human genome, may
explain susceptibility to common genetic traits and diseases and are cur-
rently being identified on a large scale as part of the Human Genome
Project (Wang et al. 1998a).
4.1.1 Mutations in the Coding DNA Sequence Affect the Translation of
RNA into Protein and Cause Hearing Loss
There are numerous examples of missense, nonsense, deletion, insertion,
and frameshift mutations in NSHL (Table 2.3), all of which affect transla-
tion of RNA into protein. One example of a locus that has multiple mis-
sense mutations that affect protein translation is the DFNA2 region.
DFNA2 contains at least two deafness genes, KCNQ4 , which codes for a
potassium channel (Kubisch et al. 1999), and GJB3 , which codes for a gap
junction protein (Xia et al. 1998). One French family, exhibiting dominant
profound hearing loss, was found to harbor a single copy of a missense
mutation in KCNQ4 . In this family, although the remainder of the protein
is translated properly, a single glycine at amino acid 285 is changed to a
serine. This glycine residue is normally located in the potassium channel
pore, a highly conserved region of the protein. Replacement of this glycine
with a serine results in a dysfunctional potassium channel. Three additional
missense mutations have been found in KCNQ4 in Dutch and American
DFNA2 families, and in all cases, the missense mutations alter conserved
and presumably essential regions in the protein (Coucke et al. 1999).
For two dominant loci, DFNA8 and DFNA12 , missense mutations in
TECTA lead to dominant NSHL (Verhoeven et al. 1998). Interestingly, in
one Belgian family, there are two missense mutations 12 bases apart. The
mutations may interact, or only one may contribute to the disease, with the
second mutation being a rare polymorphism, since it was not detected in 40
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