Biology Reference
In-Depth Information
of the bones in the outer, middle and inner ear, as well as the differentia-
tion of the nerves and sensory regions found in the inner ear.
4.2.2 Mutations that Alter Splicing Patterns Lead to Inner Ear Defects
The processing of primary RNA transcripts to remove intronic sequences
is essential. For proper splicing to occur, small nuclear ribonucleoproteins
recognize short specific sequences at the junctions between introns and
exons (usually GT at the 5¢ end of the intron and AG at the 3¢ end of the
intron) (Fig. 2.4). It has been found that mutations that alter these con-
sensus sequences alter splicing patterns. Splice-site mutations can result in
exon skipping, whereby the resulting mRNA is missing a coding exon.
Splice-site mutations can also lead to the inclusion of intronic sequences
within the mRNA. In both cases, the resulting mRNA is often nonfunc-
tional. The incorrectly spliced mRNA may encode a protein with an inter-
nal deletion as a result of exon skipping, in frame. Alternatively, and more
commonly, the incorrectly spliced mRNA can result in the addition of
improper amino acid sequences to the protein, as well as termination of
translation resulting in a truncated protein product.
Mutations that affect both the 5¢ donor and 3¢ acceptor splice sites, as well
as mutations that affect intermediates in the splicing process, have been
observed in both syndromic and nonsyndromic deafness genes. An example
of an array of splice site mutations found in one gene, myosin VIIa
(
MYO7A
), is shown in Table 2.5. Interestingly, in this case, splice-site muta-
tions can yield different phenotypes: in some cases the mutations result
in Usher syndrome type 1B, a syndromic form of deafness with retinitis
pigmentosa, whereas in other cases the mutations lead to nonsyndromic
deafness (
DFNB
2). Clearly, different tissues have different sensitivities to
alterations at splice acceptor and donor sites.
Splicing defects can also be responsible for dominant deafness. The dom-
inantly inherited progressive hearing loss (
DFNA1
) seen in a large kindred
from Costa Rica is due to a transversion in the splice donor of an exon of
the diaphanous gene (Lynch et al. 1997). The observed G to T transversion
disrupts the consensus AG sequence at the 5¢ splice donor of the next to
last exon. A shift in the open reading frame results and 21 novel amino
acids are added to the protein before the peptide is truncated prematurely.
This truncated protein acts in a dominant fashion to disrupt hearing.
Diaphanous is a member of the formin family of proteins and may have a
function in the cell cytoskeleton.
4.2.3 Deafness Mutations May Result in mRNA Destabilization
One last way that gene transcription can be altered by mutation is by the
destabilization of the mRNA itself. Even small mutations can produce
mRNAs that are degraded in the cell, resulting in a phenotype that is equiv-
alent to a total gene deletion. One such example is seen for the mouse
