Alternatively Spliced Genes
153
cause disease phenotypes. Molecular ge-
netic
studies
of
human
diseases
have
revealed a wide range of mutations that
cause diseases because of their effects
on pre-mRNA splicing. Investigating the
molecular
nature
of
these
genetic
de-
fects and pathogenetic mechanisms will
facilitate
both
diagnosis
of
such
dis-
eases and development of new therapeutic
approaches.
3.1
Splicing Defects in Human Diseases
Genetic defects that cause aberrant pre-
mRNA splicing can be found in every
category of disease, from malignancies af-
fecting a certain tissue or organ to diseases
or syndromes involving multiple systems.
Splicing mutations have been identiFed
in genes involved in the pathogenesis
of diseases in every system. Detailed in-
formation about these mutations can be
found
in
databanks
including
HGMD
(the Human Gene Mutation Database,
as
well as in a large number of publications.
A
sshowninT
ab
l
e4
,w
eu
s
eaf
ewe
x
-
amples to illustrate the diverse range of
disease phenotypes and genes involved.
The current understanding of these splic-
ing defects will be summarized.
Malignancies are a major cause of mor-
tality. Splicing mutations in genes critical
foreithercellproliferationorcelldeathre-
sult in malignancies in different systems.
These include oncogenes, tumor suppres-
sor genes, and genes involved in cell death.
Only a few examples are included here
to demonstrate the complexity of the in-
volvement of defective/aberrant splicing
in tumorigenesis. Cancer of the same tis-
sue or organ can be caused by splicing
mutations in different genes. ±or exam-
ple, splicing defects in p53, p51, CD44,
and members of epidermal growth factor
receptor (EG±R) family lead to lung can-
cer, the most common cancer in humans.
Breast cancer has been associated with
splicing mutations in a number of genes,
including HER-2/neu, p53, mdm2, and
BRCA1 or BRCA2. Glioblastomas are also
associated with splicing mutations in dif-
ferent genes. On the other hand, splicing
defects in a single gene can lead to tumori-
genesis in different tissues. ±or example,
CD44 aberrant splicing has been associ-
ated with the development of a range of
different tumors, such as breast cancer,
prostate cancer, lung cancer, and Wilm’s
tumor. CD44 is a polymorphic family of
cell surface glycoproteins important for
cell
adhesion
and
migration.
Aberrant
splicing
of
CD44
has
been
associated
with the invasive behavior and metasta-
sis of several types of tumors. Alternative
CD44 splicing variants have been corre-
lated with the poor prognosis of tumors.
Another gene is Mdm2, whose alterna-
tive splicing defects have been implicated
in oncogenesis in multiple tissues. Onco-
genic splicing variants of Mdm2 that lack
a domain important for its function in in-
teracting with the tumor suppressor p53
have been found in breast cancer, glioblas-
toma, and rhabdomyosarcoma. Alterations
in the balance of different ±G±R2 splic-
ing isoforms have been correlated with
progression of prostate cancer. A signiF-
cant fraction of neuroFbromatosis type 1
(N±1) cases are associated with an aber-
rantly spliced N±1 gene. Production of
tumor antigens as a result of alternative
splicing has been associated with neurob-
lastoma and other tumors. The role of
these tumor antigens in the development
and metastasis of these tumors remains to
be investigated. In pediatric acute myeloid
leukemia (AML), splicing isoforms of gene
fusion transcripts produced as a result of
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