158
Alternatively Spliced Genes
frequently associated with the production
of aberrant or defective gene products.
The failure to remove introns or intron
retention is another mechanism for the
formation of truncated protein products
or the complete loss of gene function, be-
cause the inclusion of intronic sequences
often introduces premature stop codons
in gene transcripts. Finally, disturbance
in the balances among naturally occur-
ring splicing isoforms can lead to hu-
man disease. These mechanisms are not
exclusive of each other. Multiple muta-
tions acting by different mechanisms have
been found in the same genes, leading
to similar disease phenotypes. For ex-
ample, both exon skipping and cryptic
splice site activation contributing to the
formation of defective LDLR lead to hyper-
cholesterolemia. Similarly, exon skipping
or cryptic splice site usage in Fibrillin-1
gene have been associated with Marfan
syndrome.
Exon skipping can be caused by mu-
tations at the splice sites or in splicing
enhancers (either ESEs or ISEs). Transla-
tionally silent mutations can be function-
ally signi±cant in splicing. For example,
third codon changes that do not affect pep-
tide sequences have often been overlooked
as disease-causing mutations. Recently,
such mutations have been examined at
the splicing level. Such ‘‘silent’’ muta-
tions may
cause
signi±cant
disruption
in splicing,
because
defective
function
of ESEs leads to either improper exon
skipping or imbalance of natural splicing
isoforms.
Activation of cryptic splice sites in a
large number of genes has been associated
with human pathogenesis (see examples
in
Table 4).
Single-nucleotide
changes
at
the
authentic
splice
sites
result
in
inactivation of authentic splice sites. The
consequences
can
be
failures
in
exon
inclusion or intron removal in some genes,
or selection/activation of cryptic splice
sites in other genes.
Intron
retention
has
been examined
in
a
number
of
disease
genes.
The
average size of introns in human genes is
approximately 3 kbp. The retention of even
a small single intron may have catastrophic
effects on the function of the genes affected
because of the formation of defective or
truncated peptides. Alternatively, intron
retention can also cause a complete loss
of expression of the mutated genes as
a
result
of
nonsense-mediated
mRNA
decay or instability of the gene products.
Tay–Sach’s disease can be caused by either
intron retention or exon skipping in the
splicing of the
β
-hexosaminidase gene.
Disturbance in the delicate balance of
different natural splicing isoforms is now
being recognized as a common mecha-
nism for splicing diseases. It has been
identi±ed in neurodegenerative diseases,
psychiatric disorders, and other diseases.
These types of splicing defects can be
caused by point mutations at splice junc-
tions or in splicing regulatory elements
(enhancers
or
silencers)
located
both
in exon and intronic regions. FTDP-17,
caused by mutations in the human
tau
gene, is a good example of such splic-
ing defects. In addition to mutations that
affect biophysical or biochemical func-
tion of Tau proteins, a large number of
mutations that alter the ratio of natural
splicing isoforms have been identi±ed in
FTDP-17 patients. The
tau
gene under-
goes complex alternative splicing during
the development of the nervous system.
Six splicing isoforms are produced, three
containing exon 10 and three lacking exon
10. These isoforms are named Tau4R and
Tau3R respectively, because exon 10 en-
codes one of four microtubule-binding
repeats. The balance among different Tau
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