Alternatively Spliced Genes
159
isoforms is important for normal brain
function, and disruption of the balance of
Tau isoforms leads to the development
of FTDP-17. Maintaining the appropri-
ate balance of different Tau isoforms is
controlled
by
complex
interactions
be-
tween the splicing machinery and various
splicing regulatory elements in the
tau
gene. At the 5
0
splice site of exon 10,
a stem-loop type of secondary structure
modulates the recognition of this 5
0
splice
site by U1snRNP. A number of intronic or
exonic mutations destabilizing this stem-
loop structure leads to an increase in
Tau4R production. Other regulatory ele-
ments residing in exon 10, either splicing
enhancers or silencers, may be disrupted
by point mutations or small deletions,
leading to the imbalance of different Tau
isoforms. These mutations may increase
(such as N279K) or decrease (such as
L284L, del280K) the activity of the exonic
splicing enhancer.
Other examples of diseases caused by
disruption of the balance of different al-
ternative splicing isoforms include Frasier
syndrome, familial isolated growth hor-
mone de±ciency type II (IGHD II) and
atypical cystic ±brosis. Such splicing de-
fects have also been implicated in the
pathogenesis of other diseases such as
multiple sclerosis and schizophrenia. In
Frasier syndrome, intronic mutations are
found
to
change
the
ratio
of
+
KTS
to – KTS isoforms of Wilms tumor sup-
pressor (WT1) gene products. The for-
mation of these two splicing isoforms
is the result of selection of two com-
peting 5
0
splice sites in exon 9. These
two splice sites are separated by 9 nu-
cleotides encoding KTS (lysine-threonine-
serine). The use of the upstream and the
downstream 5
0
splice sites produces – KTS
and
+
KTS
isoforms,
and
the
balance
of these isoforms is important for kid-
ney and gonad development. Mutations
that decrease the use of the downstream
+
KTS 5
0
splice site with an increase in
the – KTS isoform have been associated
with the majority of Frasier syndrome
cases. These examples clearly show the sig-
ni±cant role of splicing defects in human
pathogenesis.
Spinal muscular atrophy (SMA) is an
example that demonstrates the complex-
ity of mechanisms underlying diseases
caused by defects in trans-acting factors,
such as proteins essential for spliceoso-
mal snRNP biogenesis. SMA is a leading
cause of infant mortality. Pathologically, it
is characterized by degeneration of motor
neurons in the anterior horn of the spinal
cord leading to muscular atrophy. Genetic
defects causing SMA include deletions or
mutations in the survival of motor neu-
ron genes (SMN). There are two copies
of highly homologous SMN genes in hu-
mans,
SMN1
and
SMN2
.The
SMN1
gene
is deleted or mutated in the majority of
SMA patients. The SMN proteins are de-
tected as distinctive speckles termed
gems
within the nucleus. SMN proteins con-
tain an RNP1 motif and are critical for
snRNP biogenesis and therefore, the for-
mation of the spliceosome. Both SMN
genes are expressed in a wide range of
tissues. Although the predicted peptide
sequences of
SMN1
and
SMN2
genes
are identical, the gene products produced
from the two genes in cells are different.
A single translationally silent C to T nu-
cleotide change at position
+
6o
fexon7
leads to the inef±cient inclusion of exon
7inth
e
SMN2
gene product, and thus
the failure of
SMN2
to replace the func-
tion of
SMN1
and to provide protection
against SMA. It is not clear why muta-
tions in the
SMN
gene speci±cally cause
motor neuron–speci±c disease. Although
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