Alternatively Spliced Genes
157
the formation of defective gene products
and consequently the disease phenotypes.
3.2
Molecular Mechanisms Underlying Splicing
Defects Associated with Disease
Genetic defects in pre-mRNA splicing that
cause human diseases can be classiFed
into two categories, cis-acting mutations
that alter expression or function of single
genes and trans-acting defects that affect
the components of splicing machinery or
regulators of alternative splicing. Both cis-
acting and trans-acting splicing mutations
can result in clinical manifestations, either
primarily involving a single tissue/organ
or affecting multiple systems. These mu-
tations can cause diseases by their direct
effects on single genes or by indirect mech-
anisms such as disrupting expression or
regulation of multiple genes.
Cis-acting splicing mutations can cause
diseases
by
either
producing
defec-
tive/aberrant transcripts or by simply al-
tering the delicate balance of different
naturally expressed splicing isoforms. De-
velopment of disease phenotypes can be
th
er
e
su
l
to
flo
s
so
ffun
c
t
iono
fth
ein
-
volved genes or gain-of-function toxicities
associated with the aberrant gene prod-
ucts. A large number of studies have
focused
on
relationships
between
cis-
acting
splicing
mutations
and
speciFc
d
e
f
e
c
t
sinth
ef
o
rm
a
t
iono
rfun
c
t
iono
f
the affected genes. However, the relation-
ship is much less understood between
genetic defects in trans-acting splicing fac-
tors (such as spliceosomal components or
splicing regulators) and speciFc disease
phenotypes.
At least four types of molecular mech-
anisms have been described for cis-acting
splicing mutations that cause human dis-
eases (±ig. 6). These mutations often lead
to the formation of defective protein prod-
ucts or the loss of function of the genes
involved as a result of RNA or protein insta-
bility. Exon skipping is perhaps the most
commonly reported mechanism for the
production of defective gene products. Ac-
tivation of cryptic splice sites has also been
Exon
Exon
Exon skipping
X
X
X
X
Intron
Intron
X
Intron retention
X
X
X
Cryptic SS activation
*
*
3
SS
*
*
5
SS
or
Exon
Exon
X
X
X
X
X
X
Imbalance of splicing isoforms
Exon
Fig. 6
Mechanisms for cis-acting splicing mutations. Positions of mutations
are marked by ‘‘X,’’ and they can be at the splice sites or within intronic or exonic
sequences. The cryptic splice sites are marked by ‘‘*.’’ Normal splicing events
are illustrated by solid lines, and aberrant splicing events are depicted in
dotted lines.
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