156
Alternatively Spliced Genes
of a defective receptor, such as the low-
density lipoprotein receptor (LDLR), lead
to familial hypercholesterolemia (FH). A
single-nucleotide change altering the func-
tion of intracellular signal transduction
molecules can cause diseases affecting
multiple systems. For example, a single-
nucleotide polymorphism leading to the
formation of a G-protein beta3 subunit
splice variant has been associated with hy-
pertension. Aberrant or defective splicing
can disrupt the function of genes encod-
ing a wide range of proteins important for
the function of the cardiovascular system,
from cell surface receptors to intracellular
signaling molecules. Both structural genes
and regulatory genes can be affected by
splicing mutations. These examples show
that splicing mutations can affect devel-
opment/formation of the cardiovascular
system and regulation of cardiovascular
system function.
A range of metabolic diseases is caused
by splicing mutations, affecting the pro-
duction of a single metabolic enzyme. For
example, the glycogen storage diseases,
Sandhof’s disease, and Fabry’s disease
can be caused by the usage of a sin-
gle cryptic splice site in the correspond-
ing genes. Hereditary tyrosinemia (type
I) and acute intermittent porphyria can
develop because of improper exon skip-
ping in the genes encoding for respective
metabolic enzymes.
The critical role of splicing regulation
for the normal function of the nervous
system
is
demonstrated
by
the
large
number of neurodegenerative and psy-
chiatric disorders associated with aberrant
splicing. Splicing defects in
tau
and pre-
senilin
genes
have
been
identi±ed
in
different
types
of
dementia,
including
frontotemporal dementia with parkinson-
ism linked to chromosome 17 (FTDP-17)
and Alzheimer’s disease. Splicing muta-
tions that cause cryptic splice site usage
in the ataxia telangiectasia (ATM) gene
have been identi±ed in ATM patients.
Multiple
sclerosis
has
been
associated
with imbalances of different splicing iso-
forms of CD45. A number of studies have
shown that genetic mutations in ubiqui-
tously expressed protein factors that affect
spliceosome formation can lead to diseases
with speci±c neurological manifestations,
such as spinal muscular atrophy and retini-
tis pigmentosa. For example, mutations
in SMN1 or SMN2 cause spinal muscu-
lar atrophy. Defects in genes essential for
spliceosomal assembly, including HPRP3,
PRPF31, and PRPC8, have been found in
autosomal dominant retinitis pigmentosa.
The molecular mechanisms underlying
such neuronal-speci±c diseases caused by
defects in the general splicing factors re-
main to be investigated.
Psychiatric disorders, including atten-
tion de±cit/hyperactivity disorder (ADHD)
and
schizophrenia,
have
been
associ-
ated with aberrant splicing. Imbalance
of different splicing isoforms or aberrant
splicing products of several genes were
detected in the brain tissues of patients
with schizophrenia. These genes include
GABA
A
R
γ
2,
NMDAR1, neuronal
nico-
tinic acetylcholine receptors, and neural
cell adhesion molecule (NCAM). Changes
in splicing isoforms of astroglial AMPA
receptors have also been reported in hu-
man temporal lobe epilepsy. Several other
examples of diseases caused by splicing
mutations or disregulation of alternative
splicing are listed in Table 1, including
cystic ±brosis, familial isolated growth
hormone de±ciency type II (IGHD II),
Frasier’s syndrome, Menkes disease,
β
-
thalassemia, and metachromatic leukodys-
trophy. Again, a variety of aberrant splicing
events in the corresponding genes cause
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