Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3280-3288
REVIEW ARTICLE
Translational pathophysiology: a novel molecular mechanism of
human disease
Mario Cazzola and
Radek C. Skoda
From the Department of Hematology, University of Pavia Medical
School and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
Policlinico S. Matteo, Pavia, Italy; and Clinical Cooperation Unit for
Molecular Hematology-Oncology, German Cancer Research Center (DKFZ),
and Department of Medicine V, University of Heidelberg, Heidelberg,
Germany.
 |
Abstract |
In higher eukaryotes, the expression of about 1 gene in 10 is
strongly regulated at the level of messenger RNA (mRNA) translation into protein. Negative regulatory effects are often mediated by the 5'-untranslated region (5'-UTR) and rely on the
fact that the 40S ribosomal subunit first binds to the cap
structure at the 5'-end of mRNA and then scans for the first AUG
codon. Self-complementary sequences can form stable stem-loop
structures that interfere with the assembly of the preinitiation
complex and/or ribosomal scanning. These stem loops can be further
stabilized by the interaction with RNA-binding proteins, as in the case
of ferritin. The presence of AUG codons located upstream of the
physiological start site can inhibit translation by causing premature
initiation and thereby preventing the ribosome from reaching the
physiological start codon, as in the case of thrombopoietin (TPO).
Recently, mutations that cause disease through increased or decreased
efficiency of mRNA translation have been discovered, defining
translational pathophysiology as a novel mechanism of human disease.
Hereditary hyperferritinemia/cataract syndrome arises from various
point mutations or deletions within a protein-binding sequence in the 5'-UTR of the L-ferritin mRNA. Each unique mutation confers a characteristic degree of hyperferritinemia and severity of cataract in
affected individuals. Hereditary thrombocythemia (sometimes called
familial essential thrombocythemia or familial thrombocytosis) can be
caused by mutations in upstream AUG codons in the 5'-UTR of the
TPO mRNA that normally function as translational repressors. Their
inactivation leads to excessive production of TPO and elevated platelet
counts. Finally, predisposition to melanoma may originate from
mutations that create translational repressors in the 5'-UTR of
the cyclin-dependent kinase inhibitor-2A gene.
(Blood. 2000;95:3280-3288)
© 2000 by The American Society of Hematology.
| |
Introduction |
Most human genetic disorders are caused by mutations
affecting the protein-coding regions of genes, eg, missense or
frame-shift mutations within exons or mutations within introns
that disrupt pre-messenger RNA (pre-mRNA) processing.1
Dysregulated gene expression at the level of transcription is another
well-known, although less frequently encountered, mechanism in human
disease.2 Recently, mutations that cause disease through
increased or decreased efficiency of mRNA translation have been
discovered, defining translational pathophysiology as a novel mechanism
of human disease.
Translation of mRNA into protein was known to be a necessary and
important step in gene expression, but until recently was largely
considered to be a constitutive process. In the last few years,
however, a variety of regulatory mechanisms acting at the level of
translation have been discovered.3 In higher eukaryotes, the expression of about 1 gene in 10 is strongly regulated at this
level. Translational control enables a cell to increase the concentration of a protein very rapidly and therefore appears to be
especially suited to regulate genes implicated in cell proliferation and damage prevention.3 This article will review some of
the basic molecular mechanisms involved in the regulation of
translational efficiency and will illustrate the emerging principles of
translational pathophysiology by describing the first examples of human
disease attributable to mutations in mRNA regulatory sites.
Translational control of gene
expression
The presence of equal amounts of different mRNA species
does not necessarily ensure synthesis of equivalent quantities of the
corresponding proteins. In fact, some mRNAs that reach the cytoplasm
are not translated at all. Thus, negative or positive controls can
influence the rate of translation.3 These controls can be
exerted either by a global machinery that simultaneously affects all
cellular mRNAs or by more specific mechanisms that influence individual
mRNAs or subsets of mRNAs.4,5
Global control of translation is mediated by posttranslational
modifications of initiation factors and ribosomal proteins. This type
of control is especially important in early embryogenesis and during
specific stages of the cell cycle. In contrast, the specific mechanisms
operate through sequence motifs (cis-acting elements) in the mRNA
untranslated regions (UTRs). The best-studied examples of translational
regulation are mediated by the 5'-UTR and involve the control of
translation initiation. The 3'-UTR most often affects
translation indirectly by determining mRNA stability (eg, transferrin
receptor; see "Translational control by proteins that bind stem-loop
structures"). However, direct effects of the 3'-UTR on
translation initiation or polyadenylation have also been
described.6
| |
Negative regulatory elements in the 5'-UTR can interfere with
initiation of translation |
The majority of eukaryotic mRNAs are translated according
to the scanning model of translation (Figure
1). A preinitiation complex consisting of
the ribosomal 40S subunit and several initiation factors (IFs) is
assembled at the 5'-cap structure of mRNA (cap-dependent mechanism of initiation). This initiation complex then migrates along
the 5'-UTR in search of an appropriate initiator AUG codon (scanning process). Recognition of an AUG leads to assembly of the 60S
ribosomal subunit and initiation of protein synthesis. Sequence-specific inhibition of translation is mediated by negative regulatory elements present in the 5'-UTR of individual mRNAs that interfere with efficient translation initiation at the
physiological start site. Two main categories of negative regulatory
elements are known: secondary structure of mRNA and upstream open
reading frames (uORFs) in the 5'-UTR (Figure
2; Table
1).7-41
View larger version (27K):
[in this window]
[in a new window]
| Fig 1.
Main steps in translation of eukaryotic mRNA.
(A) mRNAs display two structural features that are important for
translation initiation: the methylated cap at the 5' end (yellow
pentagon) and the AUG initiation codon at the start of the coding
region (blue box). The distance between the 5'-cap and the
initiator AUG may range from about 40 to more than 1000 bases, although
it usually is less than 100 bases. (B) A preinitiation complex
consisting of the ribosomal 40S subunit (green) and several initiation
factors (IFs) is assembled at the the methylated 5'-cap. This
initiation complex then migrates along the 5'-UTR in search of an
AUG initiation codon (scanning process). (C) Recognition of an AUG
leads to assembly of the 60S ribosomal subunit and initiation of
protein synthesis.
|
|
View larger version (32K):
[in this window]
[in a new window]
| Fig 2.
Negative regulatory elements in the 5'-UTR of mRNA
that may repress translation.
(A) Schematic representation of mRNA with no negative regulatory
element. (B) Self-complementary sequences within the 5'-UTR can
form stable stem-loop structures (hairpins) located between the
5'-cap and the first AUG codon that interfere with assembling of
the preinitiation complex and/or with ribosomal scanning. The stem-loop
structure may be stable enough to resist the unwinding activity of the
associated helicase, thus imposing a major barrier to conventional
ribosomal scanning. (C) In some mRNAs, the stem loop can be further
stabilized by the interaction with RNA-binding proteins (red). (D) The
5'-UTR may contain AUG codons upstream of the physiological start
site (uAUG) that define short upstream ORFs (uORFs). These uAUGs can
cause premature initiation and inhibit translation by preventing the
ribosome from reaching the physiological start codon.
|
|
Self-complementary sequences within the 5'-UTR can form stable
stem-loop structures. When located near the 5'-cap, the stem loop
may interfere with the assembly of the preinitiation complex. Stem
loops located further downstream may be stable enough to resist the
unwinding activity of the ribosome-associated helicase (Figure 2B) and
thereby impose a major barrier to conventional ribosomal scanning (eg,
mRNA for human platelet-derived growth factor 2 [PDGF2]) (Table
1).8 Although less stable stem loops (free energies up to
126 kJ/mol) can be melted by the helicase,1 such
hairpins can be further stabilized by the interaction with RNA-binding
proteins (Figure 2C). In the case of mRNAs for ferritin and the
erythroid-specific 
-aminolevulinate synthase (ALAS2), association
with such RNA-binding proteins results in strong inhibition of
translation (see "Translational control by proteins that bind stem-loop structures").
The other major mechanism of translational inhibition involves
recognition of AUG codons located upstream of the physiological start
site (uAUG) by the scanning 40S subunit (Figure 2D).42 uAUGs that are followed by stop codons can cause premature
initiation and inhibit translation by preventing the
ribosome from reaching the physiological start codon (eg,
thrombopoietin [TPO], interleukin (IL)-7 and IL-15; Table 1). The
sequences of these uORFs can be irrelevant, as demonstrated extensively
for GCN4, the Jun homolog in yeast.43 By contrast, in the
case of S-adenosylmethionine-decarboxylase,44 the
2-adrenergic receptor,28 and the human cytomegalovirus gpUL4 gene,45 an additional inhibitory effect on
translation has been demonstrated for the uORF-encoded peptide.
Finally, some genes are transcribed from alternative promoters
resulting in mRNAs with variable 5'-ends that carry uAUGs in the
same reading frame as the main translational product (eg, bFGF or
c-myc). Use of such alternative
initiation sites generates products with alternative N-termini that are
either active or inactive, or that exert different functions. For
instance, the transcription factor C/EBP translated from an
upstream AUG functions as a transcriptional liver activator protein, whereas that translated from a downstream AUG behaves as a
liver inhibitory protein. In some cases, inhibition of translation can
be bypassed by initiation at internal ribosomal entry sites located
downstream of stem loops or uORFs (eg, c-myc, PDGF, or VEGF; Table 1).
| |
Translational control by proteins that bind stem-loop
structures: the control of cellular iron metabolism as an example of
highly integrated translational regulation |
Iron, as an essential constituent of ribonucleotide reductase, a key
enzyme in DNA synthesis, is required for growth and cell division.
Physiologically, the transport, cellular uptake, and storage of iron
are carried out by 3 proteins: transferrin, transferrin receptor, and ferritin. Ferritin is a protein shell with a molecular weight of about 500 kd made up of 24 subunits. The multiple forms, or
isoferritins, that can be found in human tissues are composed of
variable proportions of 2 subunits: L-ferritin (light, 19 kd, 174 residues) and H-ferritin (heavy, 21 kd, 182 aminoacids), encoded by
genes located on chromosome 11 and 19, respectively. Two other proteins, divalent metal transporter 1 (DMT1) also
called Nramp2,46 and HFE,47
mediate and regulate iron absorption.
Cellular iron homeostasis in mammalian cells is maintained by
the coordinated regulation of transferrin receptor and ferritin synthesis that occur at the translational level and is mediated by
cytoplasmic mRNA-binding proteins, known as iron regulatory proteins
(IRPs) (Figure 3).13 These
proteins are capable of sensing cellular iron status and of interacting
with mRNA stem-loop structures known as iron-responsive elements
(IREs). IREs constitute the first well-characterized family of
cis-acting noncoding regulatory sequences in eukaryotic
mRNA.12 A single functional IRE is found in the
5'-UTR of mRNAs for ferritin H and L subunits and in ALAS2. In
contrast, multiple IREs are present in the 3'-UTR of the mRNA for
transferrin receptor, and a single (nonconsensus) IRE has been recently
found in the 3' UTR of the DMT1 gene.48
View larger version (34K):
[in this window]
[in a new window]
| Fig 3.
Coordinate regulation of transferrin receptor and
ferritin synthesis through translational controls operated by the
iron-responsive elements (IREs) and by the iron regulatory proteins
IRP1 and IRP2.
Only one IRE is present in the 5'-UTR of ferritin mRNA. When
cellular iron is scarce, IRP molecules are available for binding the
5' IRE; initiation of translation is prevented; and ferritin
synthesis is inhibited. By contrast, presence of abundant intracellular
iron prevents binding of IRPs to the 5' IRE and allows efficient
mRNA translation to proceed (green arrow). Five IREs are present in the
3'-UTR of transferrin receptor (TfR) mRNA. When cellular iron is
scarce, binding of one or more IRPs to the IREs in the 3'-UTR
stabilizes TfR mRNA and increases TfR translation. Conversely, when
iron is abundant, very few IREs are occupied by IRPs, and TfR mRNA is
rapidly degraded. Adapted from Brittenham GM, Olivieri NF, Rouault TA.
Iron physiology and iron overload. Hematology 1996. The American
Society of Hematology, Orlando, FL, 1996, p. 177.
|
|
Two IRP family members, IRP1 and IRP2, have been identified
in humans.49-51 Under conditions of intracellular iron
depletion, both IRP1 and IRP2 function as RNA-binding proteins that
bind IREs with high affinity (Figure 3). The binding of an IRP to the ferritin IRE prevents the association of the 43S translation
preinitiation complex with the mRNA52 by precluding the
recruitment of the small ribosomal subunit.53 Thereby,
translation of the ferritin protein is repressed. Conversely, binding
of IRPs to the IREs in the 3'-UTR of transferrin receptor
increases the stability of mRNA and improves the efficiency of
translation. When intracellular iron concentrations rise, the IRPs
dissociate from the IREs. IRP1 may acquire a (4Fe-4S) cluster and
behave as a cytosolic aconitase.54 IRP1 exhibits
approximately 30% sequence homology to mitochondrial aconitase. IRP2
lacks aconitase activity and functions solely as an RNA-binding
protein. At elevated intracellular iron concentrations, IRP2 is
targeted for degradation by the proteasome.55
Thus, translational regulation by IRPs allows rapid and coordinated
control of proteins that are crucial for cellular iron homeostasis. When cells have adequate iron, the expression of transferrin receptors decreases and the levels of ferritin rise to
accommodate the excess iron. On the other hand, when cellular iron becomes scarce, the levels of ferritin fall while the expression of transferrin receptors increases to import more iron from the outside.
IREs can form a highly conserved stem-loop structure (Figure
4). The conserved features include a
hexanucleotide loop with the sequence CAGYCX, where Y = U or A, and X = U, C, or A (the first 5 bases are almost always CAGUG), and an upper
stem
consisting of 5 base pairsthat is separated from a lower stem
of variable length by an unpaired cytosine, which forms the bulge.
View larger version (21K):
[in this window]
[in a new window]
| Fig 4.
Secondary structure of the L-ferritin IRE.
The yellow area marks conserved features of the IRE consensus based on
the IRE sequences of all known ferritin and transferrin receptor mRNAs.
Positions of the point mutations responsible for hereditary
hyperferritinemia/cataract syndrome are shown, with the arrow
indicating the observed nucleotide substitution. In addition, the
following deletions have been described: C10-A38,64
A38-C39, and U42-G57.71 Adapted from Allerson et
al.75
|
|
Additional translational controls are likely to exist, at least for
ferritin. In fact, IL-1 and IL-6 also appear to elevate ferritin
synthesis by translational mechanisms during inflammation, and a
translational enhancer has been found in the L-ferritin mRNA
5'UTR.56 These sequences are distinct from the
IRE and similar to a consensus reported for the 5' leaders of
other acute phase response mRNAs.
| |
Hereditary hyperferritinemia/cataract syndrome as an established
model of translational pathophysiology |
Several reports in the last few years have described a new autosomal
dominant disorder called hereditary hyperferritinemia/cataract syndrome
(HHCS).57-74 This condition is characterized by a
combination of elevated serum ferritin in the absence of iron overload
and early-onset nuclear cataract.
With the use of monoclonal antibodies specific for the H- and
L-ferritin subunits, the elevated serum ferritin in HHCS patients has
been shown to be of the L-type.63 In addition, a close
relationship has been established between mononuclear-cell L-type
ferritin content and serum ferritin concentration, indicating that the excess production of ferritin in cells is directly responsible for the
hyperferritinemia. This dysregulated L-subunit synthesis was found to
result from different point mutations or deletions in the 5'-UTR
IRE of the L-ferritin gene (Figure 4). The observed molecular lesions
were shown to reduce the IRE affinity for the IRPs, which normally
inhibit ferritin mRNA translation, thereby causing increased production
of L-ferritin.
As several families with HHCS have been characterized, it has become
clear that not all patients are equally affected. Some individuals have
only slightly elevated serum ferritin and are asymptomatic for
cataract, while others have serum ferritin levels more than 10-fold
higher than normal and a history of severe cataract.63 Allerson et al75 measured the in vitro affinity of the IRPs for the mutant IREs from HHCS patients and correlated decreases in
binding affinity with clinical severity, showing close relationships with both degree of hyperferritinemia and cataract severity (Figure 5). These investigators also used thermal
denaturation methods to determine the effects of each HHCS mutation on
the thermodynamic stability of the IRE. This analysis revealed that
while some HHCS mutations lead to changes in the stability and
secondary structure of the IRE, others appear to disrupt IRP-IRE
recognition with minimal effect on IRE stability. The pathogenesis of
cataract is not yet clear. It is likely that lens opacities are not
congenital but rather develop during the first few years of
life69,74 and appear to be a consequence of the elevated
ferritin concentrations in the lens itself. In fact, Levi et
al76 have found that a large proportion of L-ferritin
accumulates as nonfunctional L-chain 24 homopolymers in HHCS cells, and
that L-chain accumulation occurs also in the lens, where it probably
induces cataract formation.
View larger version (29K):
[in this window]
[in a new window]
| Fig 5.
Correlation of serum ferritin with relative dissociation
constants (Krel) of IRP1 complexes with wild-type IRE and
IREs containing HHCS mutations.
Serum ferritin levels are maximal values observed in normal individuals
and families with HHCS. A significant relationship was found between
ferritin levels and dissociation constants: the higher the impairment
in IRE-IRP1 binding affinity, the higher the serum
ferritin.75 The relationship between degree of
hyperferritinemia and severity of cataract75 is illustrated
schematically for the reader's convenience. Modified from Allerson et
al.75
|
|
Thus, HHCS stands as a noteworthy example of translational
pathophysiology. This human genetic disorder originates from RNA mutations within a protein-binding site, and its severity is determined by the energetics of the binding interaction, which varies considerably among different mutations (Figures 4, 5). A recent report of a de novo
mutation in HHCS indicates that this disease should be searched for
even in sporadic cases of early-onset cataract formation.77
| |
uAUG codons as translational repressors: thrombopoietin as an
example of an mRNA physiologically repressed by a translational
mechanism |
The production of several proto-oncogenes, cytokines, and other
tightly regulated genes is in part controlled by the presence of uORFs
in the 5'-UTR (Table 1 and references therein). The extent of
uAUG-mediated inhibition of translation depends mainly on 2 factors.
The first prerequisite for a strong inhibitory effect is efficient
translational initiation at the uAUGs, which is strongly influenced by
the sequence context of each individual uAUG (Kozak consensus). The
rate of initiation at uAUGs rarely reaches 100%; therefore, some leaky
scanning usually occurs, maintaining a basal level of translation from
the physiological start site. The second factor determining the
efficiency of translational inhibition is the rate of ribosomal
reinitiation. After translation of the uORF and the encounter with the
uORF stop codon, the 40S ribosomal subunit may remain associated with
the mRNA and resume scanning for the next AUG codon. The rate of
reinitiation depends on the distance between the stop codon and the
next available AUG. A minimal intercistronic gap of 16 nucleotides was
shown to be required to allow ribosomal reinitiation.78
These principles are illustrated by the example of TPO mRNA (Figure
6A). Translation of TPO mRNA is strongly
inhibited by the presence of several uAUG codons in the
5'-UTR.18 Directed mutagenesis of all uAUGs in the
TPO mRNA restored full translational efficiency, demonstrating that
translational inhibition of TPO biosynthesis is entirely mediated by
uORFs. The uORF defined by the seventh uAUG was shown to exert the
strongest negative effect on translation.18 This uAUG is in
a good Kozak consensus and the uORF extends beyond the physiological
start site, thus preventing reinitiation (Figure 6A). The presence of
this uAUG and the length of the resulting uORF are conserved between
human, mouse, and rat TPO mRNAs.
View larger version (68K):
[in this window]
[in a new window]
| Fig 6.
Effect of TPO gene mutations on the composition of uORFs
in TPO mRNA.
TPO transcripts starting from the main promoter in exon 2 are shown.
Boxes numbered in italics represent exons. The uORFs are drawn as thick
red lines and are placed into one of the three reading frames (+1, 0, and 1). The TPO coding region is shown as a thick blue arrow.
Numbers indicate the order in which the uAUGs appear in the full-length
TPO mRNA (therefore, uAUGs 1 through 4 are not shown). The eighth AUG
is the physiological initiation codon. (A) Translation of normal TPO
mRNA is physiologically almost completely inhibited by the presence of
uORFs in the 5'-UTR. In particular, the uORF 7 is a potent
inhibitor of translation, most likely because of its extension beyond
the physiological start site. (B) A splice donor mutation in the Dutch
HT family causes exon 3 skipping ( E3) that deletes uORF7 and shifts
the TPO coding sequence into reading frame +1. TPO translation now
initiates from the fifth and sixth AUGs. (C) The Japanese mutation I
consists of a single G nucleotide deletion (G) that shifts the TPO
coding sequence into reading frame 1. TPO translation now
initiates from the seventh AUG. Note that both the Dutch and the
Japanese mutation I create altered TPO signal peptides, but do not
alter the sequence of the mature TPO protein. Both signal peptides
remain functionally active and promote secretion of a biologically
active TPO protein. (D) The Japanese mutation II creates a premature
stop codon in uORF7. This allows reinitiation of translation at the
physiological start site (the eighth AUG).
|
|
TPO is the most potent humoral regulator of platelet
formation.79 Physiologically, TPO serum concentrations are
very low, ranging between 0.5 and 2 pmol/L. Circulating TPO is mainly
produced by the liver and the kidneys, and TPO mRNA levels in these
organs remain unchanged during thrombocytopenia.80,81
However, it remains an open question whether TPO translation might be
up-regulated in response to increased platelet demand. Irrespective of
this possibility, translational repression is important to prevent overproduction of TPO, because the loss of this repression mechanism through germ-line mutations affecting the TPO 5'-UTR results in elevated TPO serum levels and thrombocythemia (see "Hereditary thrombocythemia as an example of uAUG-mediated translational
pathophysiology").
| |
Hereditary thrombocythemia as an example of uAUG-mediated
translational pathophysiology |
Hereditary thrombocythemia (HT) (sometimes called familial essential
thrombocythemia or familial thrombocytosis) is characterized by
sustained proliferation of megakaryocytes, resulting in elevated platelet counts and thrombotic or hemorrhagic complications. In most
kindreds, HT is inherited as an autosomal dominant trait with high
penetrance and early age of onset. The clinical features of HT are
indistinguishable from those of sporadic essential thrombocythemia (ET), a chronic myeloproliferative disorder. Hereditary syndromes resembling ET have been described in a number of
families.82-99 In 4 of these families, thrombocythemia was
found to be caused by gain of function mutations in the TPO gene, which
result in systemic TPO overproduction (Table
2). Interestingly, all 4 mutations affect
the 5'-UTR of TPO mRNA.
The question of how these mutations cause TPO overproduction was first
elucidated in a Dutch HT family (Figure 6B).82,83 Affected
family members carry a point mutation in the +1 position of the splice
donor of intron 3. This G
C transversion causes exon skipping
and results in loss of exon 3 that normally encodes a large part of the
5'-UTR. As a consequence, the mutant TPO mRNA lacks uORF7, which
normally inhibits translation.18 Furthermore, a novel
N-terminus is created by fusion of uORF5 with the TPO coding sequence.
The resulting extended N-terminus was shown to be a functional signal
peptide.83 Interestingly, an AG substitution 4 bases downstream of the Dutch mutation in splice donor 3 has been
reported in another HT-family.88 Although this mutation does not affect the most conserved residues of the splice donor, it is
expected to cause the same aberrant splicing as the Dutch mutation.
A completely different mutation was recently found in a Japanese family
with HT.84 Affected family members carry a single G-nucleotide deletion (G) in the 5'-UTR of the TPO gene
(Figure 6C). This G causes a frameshift in the 5'-UTR of TPO
mRNA, which places uORF7 in frame with the TPO coding sequence,
neutralizing the strong inhibitory effect of uORF7 and again creating a
novel N-terminus for the TPO signal peptide.85 Similar to
the Dutch mutation, this novel N-terminus still functions as a signal
peptide that can assure secretion of correctly processed, biologically active TPO protein.85 Thus, through a completely different
mutation, translational repression is lost, resulting in TPO
overproduction and thrombocythemia. Finally, in an unrelated Japanese
HT family,86 a GT mutation in the TPO
5'-UTR creates a novel stop codon, which shortens uORF7 by 42 nucleotides (Figure 6D).87 This generates a gap of 31 nucleotides between uORF7 and the physiological TPO start codon, which
allows translational reinitiation, resulting in enhanced translational
efficiency and overproduction of TPO.87
These 4 independent TPO gene mutations illustrate the physiological
importance of the translational repression for TPO regulation. These
examples also suggest that there are no platelet-sensing mechanisms
that, under steady state conditions, are able to detect thrombocytosis
and down-regulate TPO production in patients carrying the mutations.
| |
Translational pathophysiology as a molecular basis of hereditary
predisposition to melanoma |
Several authors have documented familial inheritance in malignant
melanoma.100 Approximately 10% of malignant neoplasms of melanocytes are inherited in an autosomal dominant fashion with variable penetrance, and in about two thirds of affected families, a
chromosome 9p21 locus has been linked to this condition.
Cyclin-dependent kinase inhibitor-2A (CDKN2A) (also known as p16,
INK4, p16INK4A, and MTS1) maps to chromosome 9p21.101 This
gene encodes a cdk4/cdk6 kinase inhibitor that constrains cells from
progressing through the G1 restriction point. In the last few
years, germ-line mutations in the CDKN2A coding
sequence that result in loss of CDKN2A function have been described in
families predisposed to melanoma. In a recent study, the incidence of
CDKN2A mutations in families with 3 or more cases of melanoma and at
least 1 member with multiple primary melanomas was found to be about
30%.102 A considerable proportion of mutation-negative
families nevertheless demonstrate linkage of inherited melanoma to 9p21
markers, suggesting either that the majority of mutations in the CDKN2A
gene causing malignant melanoma fall outside the CDKN2A coding sequence
or that CDKN2A is not the only chromosome 9p melanoma-susceptibility
locus.103
A subset of these kindreds with no coding-region
mutation have recently been shown to carry a GT transversion
at position 34 in the 5'-UTR of CDKN2A
mRNA.104 This mutation creates a novel uAUG and a novel
uORF that inhibits translation from the physiological start site, thus
leading to the loss of function of this allele. The G34T
mutation was not seen in controls while segregated with melanoma in
families. Individuals carrying this germ-line mutation in CDKN2A are
predisposed to melanoma through loss of heterozygosity. This study
illustrates how characterization of noncoding mutations in genes
controlling cell proliferation and differentiation may have an impact
on current efforts to identify genetic susceptibility to cancer.
| |
Other translational disorders and future perspectives |
In addition to the ferritin L-subunit, several other genes encoding
proteins involved in iron metabolism carry IREs. For instance, the mRNA
for ferritin H-subunit has a consensus IRE in the 5'-UTR. Mutations in the gene encoding the H-subunit have not yet been described, but one might expect that they would cause overproduction of
H-ferritin in a manner similar to IRE mutations in the L-subunit. The
resulting disorder might be incompatible with life according to the
studies by Picard et al,105 who showed that overexpression of the ferritin H-subunit in cultured erythroid cells markedly changed
the intracellular iron distribution. Mutations in the 5'-UTR IRE
of ALAS2 are also expected to cause ALAS2 protein overexpression, but
it is unclear whether this may have clinical relevance. The transferrin
receptor gene has 5 IREs in the 3'-UTR and a point mutation in 1 of the five 3'-UTR IREs is expected to have no impact on
transferrin receptor production. The presence of 5 IREs might itself be
the result of selection aimed at preventing defective production of
transferrin receptor.
In mice, there are 2 classes of duodenal DMT1 transcripts: 1 containing a 3'-UTR IRE, called DMT1(IRE), and 1 containing no
IRE, called DMT1(non-IRE).48 Mutations in
the 3'-UTR IRE are predicted to decrease the affinity for IRPs
and result in reduced DMT1 protein production, causing
deficient iron absorption. A large Sardinian family has been described
in which hypochromic microcytic anemia with hypoferremia is inherited
as a recessive characteristic.106 The disorder observed in
this family closely resembles the anemia found in both homozygous mk/mk
mice and Belgrade rats, which carry a glycine-to-arginine missense
mutation (G185R) in DMT1.46 However, no linkage between
anemia and highly polymorphic markers for the human DMT1 gene was found
in the Sardinian family.
The 20210 G-to-A transition in the prothrombin gene was first described
by Poort et al107 and found to be associated with both
elevated plasma prothrombin levels and a moderately increased risk for
first venous thrombotic events. This point mutation in the 3'-UTR
of the prothrombin gene may simply represent a polymorphism associated
with the increased risk for venous thrombosis. However, the possibility
that the mutation occurred in a sequence participating in the control
of mRNA translation should be investigated.
Translational mechanisms may also be involved in malignant disorders
through somatic mutations in regulatory regions of genes controlling
cell proliferation and differentiation. Thus, increased translation of
IL-15 mRNA secondary to the production of a human T-lymphotropic
virus-1 R-element fusion message that lacks many uAUGs has been shown
in a human adult T-cell leukemia line.20,108 Moreover,
enhanced translational efficiency of a novel transforming growth
factor-3 mRNA has been found in
several human breast cancer cell lines.23
Regulation of translation may also contribute to the pathogenesis of
Alzheimer disease. The amyloid precursor protein (APP) has been
associated with Alzheimer disease because it is processed into the
beta-peptide that accumulates in amyloid plaques, and also on the basis
of the observation that APP gene mutations can cause early-onset
disease. The 5'-UTR of APP mRNA contains a translational enhancer
that responds to IL-1109 and is homologous to
IL-6-responsive elements in the 5'-UTR of the
L- and H- ferritin genes.56
In conclusion, the recent molecular characterization of HHCS and HT has
opened a new chapter of translational pathophysiology. Although the 3 conditions described so far (HHCS, HT, and familial melanoma) are
caused by germ-line mutations, somatic mutations may be responsible for
translational pathophysiology as well. HHCS and HT mutations result in
overexpression of the gene products, whereas the mutation CDKN2A causes
loss of expression from the mutated allele. Translational
pathophysiology can generate considerable diversity in disease states,
as illustrated by the different HHCS-causing mutations (Figure 4).
Finally, the possibility exists that naturally occurring polymorphisms
within mRNA regulatory regions might contribute to phenotypic diversity
in normal individuals.
| |
Footnotes |
Submitted November 29, 1999; accepted February 18, 2000.
Supported in part by grants from the Italian Association for Cancer
Research (AIRC) Milan, Italy; IRCCS Policlinico S. Matteo, Pavia,
Italy, Ministero dell'Università e della Ricerca Scientifica e
Tecnologica (MURST), Rome, Italy; and Ferrata Storti Foundation, Pavia,
Italy (to M.C.); and by grants from the Swiss National Science
Foundation and the Swiss Cancer League (to R.C.S.).
Reprints: Mario Cazzola, Division of Hematology, IRCCS
Policlinico S. Matteo, 27100 Pavia, Italy; e-mail: m.cazzola{at}iol.it; or Radek C. Skoda, Clinical Cooperation Unit for Molecular
Hematology-Oncology, German Cancer Research Center (DKFZ), Im
Neuenheimer Feld 280, 69120 Heidelberg, Germany; e-mail:
r.skoda{at}dkfz.de.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
References |
1.
Lewin B.
Genes VI. Oxford, UK: Oxford University Press; 1997.
2.
Semenza GL.
Transcriptional regulation of gene expression: mechanisms and pathophysiology.
Hum Mutat.
1994;3:180-199[Medline]
[Order article via Infotrieve].
3.
Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watsond JD.
Molecular Biology of the Cell. New York, NY: Garland Publishing; 1989.
4.
Gray NK, Wickens M.
Control of translation initiation in animals.
Annu Rev Cell Dev Biol.
1998;14:399-458[Medline]
[Order article via Infotrieve].
5.
Kozak M.
Initiation of translation in prokaryotes and eukaryotes.
Gene.
1999;234:187-208[Medline]
[Order article via Infotrieve].
6.
Barabino SM, Keller W.
Last but not least: regulated poly(A) tail formation.
Cell.
1999;99:9-11[Medline]
[Order article via Infotrieve].
7.
Rao CD, Pech M, Robbins KC, Aaronson SA.
The 5' untranslated sequence of the c-sis/platelet-derived growth factor 2 transcript is a potent translational inhibitor.
Mol Cell Biol.
1988;8:284-292[Abstract/Free Full Text].
8.
Bernstein J, Sella O, Le SY, Elroy-Stein O.
PDGF2/c-sis mRNA leader contains a differentiation-linked internal ribosomal entry site (D-IRES).
J Biol Chem.
1997;272:9356-9362[Abstract/Free Full Text].
9.
Kim SJ, Park K, Koeller D, et al.
Post-transcriptional regulation of the human transforming growth factor-beta 1 gene.
J Biol Chem.
1992;267:13702-13707[Abstract/Free Full Text].
10.
Grens A, Scheffler IE.
The 5'- and 3'-untranslated regions of ornithine decarboxylase mRNA affect the translational efficiency.
J Biol Chem.
1990;265:11810-11816[Abstract/Free Full Text].
11.
Manzella JM, Blackshear PJ.
Regulation of rat ornithine decarboxylase mRNA translation by its 5'-untranslated region.
J Biol Chem.
1990;265:11817-11822[Abstract/Free Full Text].
12.
Theil E.
Iron regulatory elements (IREs): a family of mRNA non-coding sequences.
Biochem J.
1994;304:1-11.
13.
Klausner RD, Rouault TA, Harford JB.
Regulating the fate of mRNA: the control of cellular iron metabolism.
Cell.
1993;72:19-28[Medline]
[Order article via Infotrieve].
14.
Gunshin H, Mackenzie B, Berger UV, et al.
Cloning and characterization of a mammalian proton-coupled metal-ion transporter.
Nature.
1997;388:482-488[Medline]
[Order article via Infotrieve].
15.
Nielsen FC, Ostergaard L, Nielsen J, Christiansen J.
Growth-dependent translation of IGF-II mRNA by a rapamycin-sensitive pathway.
Nature.
1995;377:358-362[Medline]
[Order article via Infotrieve].
16.
Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH, Wewer UM, Nielsen FC.
A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development.
Mol Cell Biol.
1999;19:1262-1270[Abstract/Free Full Text].
17.
Rogers JT, Leiter LM, McPhee J, et al.
Translation of the Alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5'-untranslated region sequences.
J Biol Chem.
1999;274:6421-6431[Abstract/Free Full Text].
18.
Ghilardi N, Wiestner A, Skoda RC.
Thrombopoietin production is inhibited by a translational mechanism.
Blood.
1998;92:4023-4030[Abstract/Free Full Text].
19.
Namen AE, Lupton S, Hjerrild K, et al.
Stimulation of B-cell progenitors by cloned murine interleukin-7.
Nature.
1988;333:571-573[Medline]
[Order article via Infotrieve].
20.
Bamford RN, Battiata AP, Burton JD, Sharma H, Waldmann TA.
Interleukin (IL) 15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type I region /IL-15 fusion message that lacks many upstream AUGs that normally attenuates IL-15 mRNA translation.
Proc Natl Acad Sci U S A.
1996;93:2897-2902[Abstract/Free Full Text].
21.
Nishimura H, Washizu J, Nakamura N, Enomoto A, Yoshikai Y.
Translational efficiency is up-regulated by alternative exon in murine IL-15 mRNA.
J Immunol.
1998;160:936-942[Abstract/Free Full Text].
22.
Arrick BA, Lee AL, Grendell RL, Derynck R.
Inhibition of translation of transforming growth factor-beta 3 mRNA by its 5' untranslated region.
Mol Cell Biol.
1991;11:4306-4313[Abstract/Free Full Text].
23.
Arrick BA, Grendell RL, Griffin LA.
Enhanced translational efficiency of a novel transforming growth factor beta 3 mRNA in human breast cancer cells.
Mol Cell Biol.
1994;14:619-628[Abstract/Free Full Text].
24.
Huez I, Creancier L, Audigier S, Gensac MC, Prats AC, Prats H.
Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA.
Mol Cell Biol.
1998;18:6178-6190[Abstract/Free Full Text].
25.
Harigai M, Miyashita T, Hanada M, Reed JC.
A cis-acting element in the BCL-2 gene controls expression through translational mechanisms.
Oncogene.
1996;12:1369-1374[Medline]
[Order article via Infotrieve].
26.
Phelps DE, Hsiao KM, Li Y, et al.
Coupled transcriptional and translational control of cyclin-dependent kinase inhibitor p18INK4c expression during myogenesis.
Mol Cell Biol.
1998;18:2334-2343[Abstract/Free Full Text].
27.
Mize GJ, Ruan H, Low JJ, Morris DR.
The inhibitory upstream open reading frame from mammalian S-adenosylmethionine decarboxylase mRNA has a strict sequence specificity in critical positions.
J Biol Chem.
1998;273:32500-325005[Abstract/Free Full Text].
28.
Parola AL, Kobilka BK.
The peptide product of a 5' leader cistron in the beta 2 adrenergic receptor mRNA inhibits receptor synthesis.
J Biol Chem.
1994;269:4497-4505[Abstract/Free Full Text].
29.
McGraw DW, Forbes SL, Kramer LA, Liggett SB.
Polymorphisms of the 5' leader cistron of the human beta2-adrenergic receptor regulate receptor expression.
J Clin Invest.
1998;102:1927-1932[Medline]
[Order article via Infotrieve].
30.
Ossipow V, Descombes P, Schibler U.
CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials.
Proc Natl Acad Sci U S A.
1993;90:8219-8223[Abstract/Free Full Text].
31.
Descombes P, Schibler U.
A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA.
Cell.
1991;67:569-579[Medline]
[Order article via Infotrieve].
32.
Acland P, Dixon M, Peters G, Dickson C.
Subcellular fate of the int-2 oncoprotein is determined by choice of initiation codon.
Nature.
1990;343:662-665[Medline]
[Order article via Infotrieve].
33.
Florkiewicz RZ, Sommer A.
Human basic fibroblast growth factor gene encodes four polypeptides: three initiate translation from non-AUG codons.
Proc Natl Acad Sci U S A.
1989;86:3978-3981[Abstract/Free Full Text].
34.
Prats H, Kaghad M, Prats AC, et al.
High molecular mass forms of basic fibroblast growth factor are initiated by alternative CUG codons.
Proc Natl Acad Sci U S A.
1989;86:1836-1840[Abstract/Free Full Text].
35.
Arnaud E, Touriol C, Boutonnet C, et al.
A new 34-kilodalton isoform of human fibroblast growth factor 2 is cap dependently synthesized by using a non-AUG start codon and behaves as a survival factor.
Mol Cell Biol.
1999;19:505-514[Abstract/Free Full Text].
36.
Hann SR, King MW, Bentley DL, Anderson CW, Eisenman RN.
A non-AUG translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas.
Cell.
1988;52:185-195[Medline]
[Order article via Infotrieve].
37.
Hann SR, Sloan-Brown K, Spotts GD.
Translational activation of the non-AUG-initiated c-myc 1 protein at high cell densities due to methionine deprivation.
Genes Dev.
1992;6:1229-1240[Abstract/Free Full Text].
38.
Carter PS, Jarquin-Pardo M, De Benedetti A.
Differential expression of Myc1 and Myc2 isoforms in cells transformed by eIF4E: evidence for internal ribosome repositioning in the human c-myc 5'UTR.
Oncogene.
1999;18:4326-4335[Medline]
[Order article via Infotrieve].
39.
Saris CJ, Domen J, Berns A.
The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG.
EMBO J.
1991;10:655-664[Medline]
[Order article via Infotrieve].
40.
Packham G, Brimmell M, Cleveland JL.
Mammalian cells express two differently localized Bag-1 isoforms generated by alternative translation initiation.
Biochem J.
1997;328:807-813.
41.
Yang X, Pater A, Tang SC.
Cloning and characterization of the human BAG-1 gene promoter: upregulation by tumor-derived p53 mutants.
Oncogene.
1999;18:4546-4553[Medline]
[Order article via Infotrieve].
42.
Kozak M.
Interpreting cDNA sequences: some insights from studies on translation.
Mamm Genome.
1996;7:563-574[Medline]
[Order article via Infotrieve].
43.
Miller PF, Hinnebusch AG.
cis-Acting sequences involved in the translational control of GCN4 expression.
Biochim Biophys Acta.
1990;1050:151-154[Medline]
[Order article via Infotrieve].
44.
Ruan H, Shantz LM, Pegg AE, Morris DR.
The upstream open reading frame of the mRNA encoding S-adenosylmethionine decarboxylase is a polyamine-responsive translational control element.
J Biol Chem.
1996;271:29576-29582[Abstract/Free Full Text].
45.
Cao J, Geballe AP.
Inhibition of nascent-peptide release at translation termination.
Mol Cell Biol.
1996;16:7109-7114[Abstract].
46.
Su MA, Trenor CC, Fleming JC, Fleming MD, Andrews NC.
The G185R mutation disrupts function of the iron transporter Nramp2.
Blood.
1998;92:2157-2163[Abstract/Free Full Text].
47.
Zhou XY, Tomatsu S, Fleming RE, et al.
HFE gene knockout produces mouse model of hereditary hemochromatosis.
Proc Natl Acad Sci U S A.
1998;95:2492-2497[Abstract/Free Full Text].
48.
Fleming RE, Migas MC, Zhou X, et al.
Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1.
Proc Natl Acad Sci U S A.
1999;96:3143-3148[Abstract/Free Full Text].
49.
Rouault TA, Hentze MW, Haile DJ, Harford JB, Klausner RD.
The iron-responsive element binding protein: a method for the affinity purification of a regulatory RNA-binding protein.
Proc Natl Acad Sci U S A.
1989;86:5768-5772[Abstract/Free Full Text].
50.
Haile DJ, Hentze MW, Rouault TA, Harford JB, Klausner RD.
Regulation of interaction of the iron-responsive element binding protein with iron-responsive RNA elements.
Mol Cell Biol.
1989;9:5055-5061[Abstract/Free Full Text].
51.
Samaniego F, Chin J, Iwai K, Rouault TA, Klausner RD.
Molecular characterization of a second iron-responsive element binding protein, iron regulatory protein 2: structure, function, and post-translational regulation.
J Biol Chem.
1994;269:30904-30910[Abstract/Free Full Text].
52.
Gray NK, Hentze MW.
Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs.
EMBO J.
1994;13:3882-3891[Medline]
[Order article via Infotrieve].
53.
Muckenthaler M, Gray NK, Hentze MW.
IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F.
Mol Cell.
1998;2:383-388[Medline]
[Order article via Infotrieve].
54.
Haile DJ, Rouault TA, Tang CK, Chin J, Harford JB, Klausner RD.
Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster.
Proc Natl Acad Sci U S A.
1992;89:7536-7540[Abstract/Free Full Text].
55.
Iwai K, Drake SK, Wehr NB, et al.
Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins.
Proc Natl Acad Sci U S A.
1998;95:4924-4928[Abstract/Free Full Text].
56.
Rogers JT.
Ferritin translation by interleukin-6: the role of sequences upstream of the start codons of the heavy and light subunit genes.
Blood.
1996;87:2525-2537[Abstract/Free Full Text].
57.
Girelli D, Oliviero O, De Franceschi L, Corrocher R, Bergamaschi G, Cazzola M.
A linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract.
Br J Haematol.
1995;90:931-934[Medline]
[Order article via Infotrieve].
58.
Bonneau D, Winter-Fuseau I, Loiseau M-N, et al.
Bilateral cataract and high serum ferritin: a new dominant genetic disorder?
J Med Genet.
1995;32:778-779[Abstract/Free Full Text].
59.
Beaumont C, Leneuve P, Devaux I, et al.
Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract.
Nature Genet.
1995;11:444-446[Medline]
[Order article via Infotrieve].
60.
Girelli D, Corrocher R, Bisceglia L, et al.
Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the "Verona mutation").
Blood.
1995;86:4050-4053[Abstract/Free Full Text].
61.
Aguilar-Martinez P, Biron C, Masmejean C, Jeanjean P, Schved J-F.
A novel mutation in the iron responsive element of ferritin l-subunit gene as a cause for hereditary hyperferritinemia-cataract syndrome [letter].
Blood.
1996;88:1895[Free Full Text].
62.
Merkt J.
Hereditary hyperferritinemia-cataract syndrome.
Dtsch Med Wochenschr.
1997;122:504-506[Medline]
[Order article via Infotrieve].
63.
Cazzola M, Bergamaschi G, Tonon L, et al.
Hereditary hyperferritinemia-cataract syndrome: relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA.
Blood.
1997;90:814-821[Abstract/Free Full Text].
64.
Girelli D, Corrocher R, Bisceglia L, et al.
Hereditary hyperferritinemia-cataract syndrome caused by a 29-base pair deletion in the iron responsive element of ferritin L-subunit gene.
Blood.
1997;90:2084-2088[Abstract/Free Full Text].
65.
Arnold JD, Mumford AD, Lindsay JO, Hegde U, Hagan M, Hawkins JR.
Hyperferritinaemia in the absence of iron overload.
Gut.
1997;41:408-410[Abstract/Free Full Text].
66.
Martin ME, Fargion S, Brissot P, Pellat B, Beaumont C.
A point mutation in the bulge of the iron-responsive element of the L ferritin gene in two families with the hereditary hyperferritinemia-cataract syndrome.
Blood.
1998;91:319-323[Abstract/Free Full Text].
67.
Mumford AD, Vulliamy T, Lindsay J, Watson A.
Hereditary hyperferritinemia-cataract syndrome: two novel mutations in the L-ferritin iron-responsive element [letter].
Blood.
1998;91:367-369[Free Full Text].
68.
Cicilano M, Zecchina G, Roetto A, et al.
Recurrent mutations in the IRE of L-ferritin in hereditary hyperferritinemia-cataract syndrome.
Haematologica.
1999;84:489-492[Abstract/Free Full Text].
69.
Balas A, Aviles MJ, Garcia-Sanchez F, Vicario JL.
Description of a new mutation in the L-ferrin iron-responsive element associated with hereditary hyperferritinemia-cataract syndrome in a Spanish family [letter].
Blood.
1999;93:4020-4021[Free Full Text].
70.
Cremonesi L, Fumagalli A, Soriani N, et al.
Development of a DG-DGGE method for rapid mutational scanning in ferritin L-chain IRE: an approach for screening of hereditary hyperferritinemia cataract syndrome (HHCS) [abstract]. Proceedings of the World Congress on Iron Metabolism. Sorrento: Italy; 1999:164.
71.
Beaumont C, Milon B, Hetet G.
Genetic studies on patients with elevated serum ferritin levels and no iron overload: evaluation at a two year recruitment [abstract]. Proceedings of the World Congress on Iron Metabolism. Sorrento: Italy; 1999:161.
72.
Brools DG, Stamboliam DE.
A novel mutation of the "bulge cytosine" in the human L ferritin iron responsive element causes hyperferritinemia/cataract syndrome [abstract]. Proceedings of the World Congress on Iron Metabolism. Sorrento: Italy; 1999:163.
73.
Kato GJ, Casella F.
L-ferritin-Baltimore-1: a novel mutation in the iron response element (C32G) as a cause of the hyperferritinemia-cataract syndrome [abstract].
Blood.
1999;94:407a.
74.
Girelli D, Zecchina G, Tinazzi E, et al.
Molecular, biochemical and clinical findings in a series of families with the hereditary hyperferritinemia-cataract syndrome. [abstract].
Blood.
1999;94:644a.
75.
Allerson CR, Cazzola M, Rouault TA.
Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome.
J Biol Chem.
1999;274:26439-26447[Abstract/Free Full Text].
76.
Levi S, Girelli D, Perrone F, et al.
Analysis of ferritins in lymphoblastoid cell lines and in the lens of subjects with hereditary hyperferritinemia-cataract syndrome.
Blood.
1998;91:4180-4187[Abstract/Free Full Text].
77.
Arosio C, Fossati L, Vigano M, Trombini P, Cazzaniga G, Piperno A.
Hereditary hyperferritinemia cataract syndrome: a de novo mutation in the iron responsive element of the L-ferritin gene.
Haematologica.
1999;84:560-561[Free Full Text].
78.
Luukkonen BG, Tan W, Schwartz S.
Efficiency of reinitiation of translation on human immunodeficiency virus type 1 mRNAs is determined by the length of the upstream open reading frame and by intercistronic distance.
J Virol.
1995;69:4086-4094[Abstract].
79.
Kaushansky K.
Thrombopoietin.
N Engl J Med.
1998;339:746-754[Free Full Text].
80.
Stoffel R, Wiestner A, Skoda RC.
Thrombopoietin in thrombocytopenic mice: evidence against regulation at the mRNA level and for a direct regulatory role of platelets.
Blood.
1996;87:567-573[Abstract/Free Full Text].
81.
Cohen-Solal K, Villeval JL, Titeux M, Lok S, Vainchenker W, Wendling F.
Constitutive expression of Mpl ligand transcripts during thrombocytopenia or thrombocytosis.
Blood.
1996;88:2578-2584[Abstract/Free Full Text].
82.
Schlemper RJ, van der Maas APC, Eikenboom JCJ.
Familial essential thrombocythemia: clinical characteristics of 11 cases in one family.
Ann Hematol.
1994;68:153-158[Medline]
[Order article via Infotrieve].
83.
Wiestner A, Schlemper RJ, van der Maas AP, Skoda RC.
An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia.
Nature Genet.
1998;18:49-52[Medline]
[Order article via Infotrieve].
84.
Kondo T, Okabe M, Sanada M, et al.
Familial essential thrombocythemia associated with one-base deletion in the 5'-untranslated region of the thrombopoietin gene.
Blood.
1998;92:1091-1096[Abstract/Free Full Text].
85.
Ghilardi N, Skoda RC.
A single-base deletion in the thrombopoietin (TPO) gene causes familial essential thrombocytosis through a mechanism of more efficient translation of TPO mRNA [letter].
Blood.
1999;94:1480-1482[Free Full Text].
86.
Kikuchi M, Tayama T, Hayakawa H, Takahashi I, Hoshino H, Ohsaka A.
Familial thrombocytosis.
Br J Haematol.
1995;89:900-902[Medline]
[Order article via Infotrieve].
87.
Ghilardi N, Wiestner A, Kikuchi M, Oshaka A, Skoda RC.
Hereditary thrombocythemia in a Japanese family is caused by a novel point mutation in the thrombopoietin gene.
Br J Haematol.
1999;107:310-316[Medline]
[Order article via Infotrieve].
88.
Jorgensen MJ, Raskind WH, Wolff JF, Bachrach HR, Kaushansky K.
Familial thrombocytosis associated with overproduction of thrombopoietin due to a novel splice donor site mutation [abstract].
Blood.
1998;92:205a
89.
Fickers M, Speck B.
Thrombocythaemia: familial occurrence and transition into blastic crisis.
Acta Haematol.
1974;51:257-265[Medline]
[Order article via Infotrieve].
90.
Slee PHTJ, van Everdingen JJE, Geraedts JPM, te Velde J, den Ottolander GJ.
Familial myeloproliferative disease.
Acta Med Scand.
1981;210:321-327[Medline]
[Order article via Infotrieve].
91.
Eyster ME, Saletan SL, Rabellino EM, et al.
Familial essential thrombocythemia.
Am J Med.
1986;80:497-502[Medline]
[Order article via Infotrieve].
92.
Fernandez-Robles E, Vermylen C, Martiat P, Ninane J, Cornu G.
Familial essential thrombocythemia.
Pediatr Hematol Oncol.
1990;7:373-376[Medline]
[Order article via Infotrieve].
93.
Janssen JW, Anger BR, Drexler HG, Bartram CR, Heimpel H.
Essential thrombocythemia in two sisters originating from different stem cell levels.
Blood.
1990;75:1633-1636[Abstract/Free Full Text].
94.
Yagisawa M, Kamizaki K, Nagase T, et al.
Familial essential thrombocythemia in a daughter and mother [in Japanese].
Nippon Naika Gakkai Zasshi.
1990;79:531-532[Medline]
[Order article via Infotrieve]
95.
Williams EC, Shahidi NT.
Benign familial thrombocytosis.
Am J Hematol.
1991;37:124-125[Medline]
[Order article via Infotrieve].
96.
Perez-Encinas M, Bello JL, Perez-Crespo S, De Miguel R, Tome S.
Familial myeloproliferative syndrome.
Am J Hematol.
1994;46:225-229[Medline]
[Order article via Infotrieve].
97.
Ulibarrena C, Vecino AM, Odriozola J, Cesar JM.
Familial essential thrombocythemia associated with von Willebrand disease [letter].
Med Clin (Barc).
1997;109:237-238[Medline]
[Order article via Infotrieve].
98.
Cohen N, Almoznino-Sarafian D, Weissgarten J, et al.
Benign familial microcytic thrombocytosis with autosomal dominant transmission.
Clin Genet.
1997;52:47-50[Medline]
[Order article via Infotrieve].
99.
Kunishima S, Mizuno S, Naoe T, Saito H, Kamiya T.
Genes for thrombopoietin and c-mpl are not responsible for familial thrombocythaemia: a case study.
Br J Haematol.
1998;100:383-386[Medline]
[Order article via Infotrieve].
100. McKusick VA et al. OMIM (database, online). Melanoma, cutaneous
malignant; CMM. Developed by National Center for Biotechnology
Information. Available at
http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?155600. Accessed
March 13, 2000.
101. McKusick VA et al. OMIM. Cyclin-dependent kinase inhibitor-2A; CDKN2A.
Developed by National Center for Biotechnology Information. Available
at http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600160. Accessed
March
13, 2000.
102.
Holland EA, Schmid H, Kefford RF, Mann GJ.
CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas.
Genes Chromosomes Cancer.
1999;25:339-348[Medline]
[Order article via Infotrieve].
103.
Kamb A, Shattuck-Eidens D, Eeles R, et al.
Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus.
Nature Genet.
1994;8:23-26[Medline]
[Order article via Infotrieve].
104.
Liu L, Dilworth D, Gao L, et al.
Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma.
Nature Genet.
1999;21:128-132[Medline]
[Order article via Infotrieve].
105.
Picard V, Renaudie F, Porcher C, Hentze MW, Grandchamp B, Beaumont C.
Overexpression of the ferritin H subunit in cultured erythroid cells changes the intracellular iron distribution.
Blood.
1996;87:2057-2064[Abstract/Free Full Text].
106.
Galanello R, Cau M, Melis MA, Deidda F, Cao A, Cazzola M.
Studies of Nramp2, transferrin receptor and transferrin genes as candidate genes for human hereditary microcytic anemia due to defective iron absorption and utilization [abstract].
Blood.
1998;92:669a.
107.
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM.
A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.
Blood.
1996;88:3698-3703[Abstract/Free Full Text].
108.
Burton JD, Bamford RN, Peters C, et al.
A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells.
Proc Natl Acad Sci U S A.
1994;91:4935-4939[Abstract/Free Full Text].
109.
Rogers JT, Leiter LM, McPhee J, et al.
Translation of the Alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5'-untranslated region sequences.
J Biol Chem.
1999;274:6421-6431.
Top
Abstract
Introduction
