*194070 WILMS TUMOR 1; WT1
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NEPHROBLASTOMA
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Gene Map Locus: 11p13
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TEXT
Rather numerous instances of multiple sibs with
Wilms tumor have been described (Fitzgerald
and Hardin, 1955). Strom
(1957) described a family with 5 cases in 3
generations. A healthy male had 2 affected children
(out of 5) by 1 wife and 1 affected child by
another wife. A sister and an aunt of his had died
in infancy or early childhood of abdominal tumor.
Jolles (1973) described
Wilms tumor in a 30-month-old girl and
hypernephroma in her 67-year-old paternal
grandmother. Brown et al.
(1972) reported the occurrence of Wilms tumor
in 4 members of 3 successive generations of a
family: the proband, a girl, her mother, aunt and
grandfather. The presence of Wilms tumor was
histopathologically confirmed in 3 of the 4 cases.
The right kidney was affected first in all. The
aunt eventually developed Wilms tumor of the left
kidney leading to her death at age 7. Matsunaga
(1981) concluded that inheritance in familial
cases, 'which constitute less than 1% of all'
cases, is autosomal dominant with variable
penetrance and expressivity. About 20% of familial
cases are bilateral; about 3% of sporadic cases are
bilateral. Bilateral cases may always be familial.
Matsunaga (1981) further
concluded that his 'host resistance model' fit the
data.
Knudson and Strong
(1972) reviewed and summarized data on 58
familial cases of Wilms tumor. They concluded that
bilateral tumors are more likely to be familial,
that familial tumors result from 2 mutations, 1
germinal and 1 somatic, and that sporadic tumors
result from 2 somatic mutations. Work of Fearon
et al. (1984), Koufos et
al. (1984), Orkin et al.
(1984), and Reeve et al.
(1984) demonstrated that homozygosity of 11p
change is present in Wilms tumor, thus providing
support for the Knudson hypothesis.
The syndrome of aniridia, hemihypertrophy and
other congenital anomalies with Wilms tumor,
subsequently known as the WAGR syndrome, was first
described by Miller et al.
(1964). Meadows et al.
(1974) described a family in which the mother
had congenital hemihypertrophy and 3 of her
children had Wilms tumor. A fourth child had a
urinary tract anomaly. In 1 of the children the
Wilms tumor was bilateral and in a second it was
multicentric. Bond (1975)
found associated congenital anomalies in 5 of 11
cases of bilateral Wilms tumor and in only 3 of 76
cases of unilateral Wilms tumor. See 235000
for discussion of familial hemihypertrophy.
Riccardi et al. (1978)
observed a triad of aniridia, ambiguous genitalia
and mental retardation (AGR triad) in 3 patients
with an interstitial deletion of the short arm of
chromosome 11. One patient also had Wilms tumor.
Among 6 cases, Francke et
al. (1978) showed that Wilms tumor was not
present in all cases, although aniridia was. For
example, between monozygotic twins with an
identical deletion of 11p, aniridia and mental
retardation were present in both and Wilms tumor in
only 1. Only 1 of the other 4 patients had Wilms
tumor. The deleted segment common to all was the
distal half of 11p13. Anderson
et al. (1978) described aniridia, cataract and
gonadoblastoma in a mentally retarded girl with an
interstitial deletion of the short arm of
chromosome 11. Gonadoblastoma occurs as part of the
WAGR complex (Junien et al.,
1980; Turleau et al.,
1981). Because of the importance of awareness
of this feature, the 'G' should stand for
gonadoblastoma. (The 'G' of WAGR has variously
meant to authors 'ambiguous genitalia' (Riccardi
et al., 1978), 'genitourinary abnormalities,'
or 'gonadoblastoma' (Anderson
et al., 1978).) The WAGR complex qualifies as a
'contiguous gene syndrome' (Schmickel,
1986); see 194072.
Apparent close linkage of the region determining
the WAGR syndrome to the catalase locus (CAT;
115500)
means that assay of catalase activity can usefully
indicate those cases of new-mutation aniridia that
should have surveillance for the development of
renal or gonadal tumors (Junien
et al., 1980). In a report that focused on the
aniridia component of the WAGR syndrome, Gilgenkrantz
et al. (1982) analyzed the reported cases of
aniridia with interstitial del(11)p. They reported
a unique observation of hypertrophic cardiomyopathy
in association with aniridia and catalase
deficiency in a patient with del(11)(p15.1p12).
Using high resolution chromosome banding, Marshall
et al. (1982) studied 14 patients with
aniridia. Seven were familial and had normal
chromosomes; of 7 sporadic cases, 1 showed normal
chromosomes and 6 had interstitial deletion of 11p
of various lengths. Band 11p13 was included in the
deletion in all 6 cases. In the cells of a Wilms
tumor, unassociated with the WAGR syndrome and with
normal constitutional chromosomes, Kaneko
et al. (1981) found an interstitial deletion
involving the region 11p14-p13.
Mapping studies by de Martinville and Francke
(1983, 1984)
appeared to rule out a close physical association
between HRAS1 and the region responsible for
predisposition to Wilms tumor. Of course, deletion
may bring them together. They placed HRAS1, HBB and
insulin in the 11p15-p14.2 segment. By somatic cell
hybridization, Junien et al.
(1984) found that HRAS1 maps to 11p15.5-p15.1.
In 4 cases of deletion of 11p13 with WAGR, they
found that the restriction enzyme digestion
patterns typical of HRAS1 were present. Thus, HRAS1
is not deleted in WAGR, a finding consistent with
the difference in mapping. Reeve
et al. (1984) demonstrated loss of HRAS
(190020)
in a sporadic case of Wilms tumor. Pointing out the
conflicting evidence on the location of HRAS, they
concluded that until the chromosomal location of
HRAS has been determined with certainty, one cannot
exclude a possible functional involvement of this
oncogene in Wilms tumor development. From gene
dosage studies, Narahara et
al. (1984) concluded that both the CAT and the
WAGR loci are in the chromosome segment
11p1306-p1305, with CAT distal to WAGR. Nakagome
et al. (1984) concluded that deletion of the
middle part of the 11p13 band is crucial to the
WAGR syndrome; others had suggested that the distal
half is of critical importance. Turleau
et al. (1984) reviewed a total of 42 cases.
Turleau et al. (1984)
suggested that the determinant of aniridia may be
separate from that for nephroblastoma, on the basis
of a boy with deletion of most of 11p13, low
catalase, nephroblastoma, chordee and
cryptorchidism but normal irides and no mental
retardation. The authors pointed out that in all
published cases with aniridia the distal half of
11p13 is deleted whereas in their presently
reported case there was 'a tiny residual distal
segment.' The observation might suggest the order
cen--CAT--WILMS--aniridia--tel; however, Narahara
et al. (1984) placed the catalase locus distal
to the WAGR locus.
Riccardi et al.
(1982) reported a patient with Wilms tumor and
iris dysplasia, not aniridia. In the UK, Shannon
et al. (1982) found the incidence of aniridia
in cases of Wilms tumor to be 1 in 43. A survey
detected 8 living and 3 dead children with Wilms
tumor and aniridia. All 8 living children had
deletion of 11p13. A high incidence of bilateral
Wilms tumor (36%), male sex, early presentation,
and advanced maternal age were features of the
combined cases. By molecular genetic studies of
cells from a patient with aniridia-Wilms tumor,
Michalopoulos et al.
(1985) concluded that a deletion visible
cytologically in 11p13 deleted the catalase loci
but not the LDHA locus, which is proximal, nor
insulin, gamma-globin loci, HRAS1 and calcitonin,
which are located distally. Among 49 children with
Wilms tumor without aniridia, only 1 had bilateral
renal tumors. By use of RFLPs that map to 11p,
Raizis et al. (1985)
detected mitotic recombination as the mechanism of
homozygosity in a Wilms tumor. Their findings
showed that insulin and beta-globin had come to
homozygosity in the tumor but PTH remained
heterozygous. Thus, PTH must be proximal to 11p13,
the cytologically determined site of the Wilms
tumor 'gene.' Scoggin et
al. (1985) showed that E7-associated
cell-surface antigen encoded by chromosome 11 and
defined by a monoclonal antibody is deleted in
cases of WAGR. This antigen is probably the same as
that previously called 'a1' (151250).
The studies in cases of WAGR with small deletions
of 11p permitted regionalization of the assignment
of antigen a1 to 11p13.
Comings (1973)
proposed that dominantly inherited tumors may arise
through inactivation or loss of a pair of
regulatory genes that normally suppress the
expression of a structural transforming gene. In 4
cases of Wilms tumor, Reeve
et al. (1985) found that transcripts of
insulin-like growth factor II (IGF2; 147470)
were highly elevated as compared with adjacent
normal kidney. Furthermore, by in situ
hybridization, they mapped the IGF2 gene to
11p14.1, close to the WAGR locus. They proposed
that IGF2 is the (or a) transforming gene in Wilms
tumor. (Their positioning of the IGF2 locus is
inconsistent with that of others who place it in a
somewhat more distal band.) Scott
et al. (1985) pointed out that Wilms tumor is
histologically indistinguishable from the early
stages of kidney development. In 12 sporadic cases
of Wilms tumor, Scott et
al. (1985), like Reeve
et al. (1985) found that expression of the IGF2
gene was markedly increased relative to adult
tissues, but was comparable to the level of
expression in several fetal tissues including
kidney, liver, adrenal, and striated muscle.
Although this may merely reflect the stage of tumor
differentiation, the possibility that IGF2 is
involved in the transformation process was raised.
Francke (1990) pointed
out that the Wilms tumor site is close to that of
IGF2, which is a candidate gene for Wilms tumor at
that site. Van Heyningen et
al. (1985) studied 5 persons with
constitutional deletions of 11p. All had aniridia;
2 had had a Wilms tumor removed. Using a cDNA probe
for catalase, they showed that the CAT locus was
deleted in 4 of 5 and that it must be proximal to
the Wilms and aniridia loci. HBB and CALC were
deleted in none; therefore, these loci are likely
to be outside the region 11p15.4-p12. A region of
11p associated with Wilms tumor has also been tied
to rhabdomyosarcoma and hepatoblastoma (Koufos
et al., 1985); see WT2 (194071).
All 3 of these rare embryonal cancers occur in the
Beckwith-Wiedemann syndrome (130650).
Kozman et al. (1989)
found loss of alleles from 11p in a Wilms tumor in
a 37-year-old male. The finding indicated a common
pathogenesis of childhood and adult types and
suggested that molecular genetic studies may be
useful in the differentiation of Wilms tumor from
renal cell carcinoma or sarcoma when the histologic
findings are unclear. Weissman
et al. (1987) explored the role of the 11p13
deletion in Wilms tumor by introducing a normal
human chromosome 11 into a Wilms tumor cell line by
means of the microcell transfer technique. The
ability of the cells containing the normal
chromosome 11 to form tumors in nude mice was
completely suppressed.
Schroeder et al.
(1987) found that in 5 patients with Wilms
tumor and 2 others previously reported, there was a
loss of chromosome 11 alleles and that these
alleles in all 7 cases were of maternal origin. All
of these tumors were sporadic. The authors
concluded that the initial mutation, either
germinal or somatic, must have occurred on the
paternal chromosome. There was no occupational
history pointing to an increased risk of mutation
in the fathers and, on the average, paternal age
was not increased. They stated that the probability
of all 7 patients losing the maternal allele in
their Wilms tumor tissues, if the loss is indeed
random, is less than 1%. By means of RFLPs,
Huff et al. (1990)
demonstrated that 7 of 8 de novo deletions of band
11p13 were of paternal origin. The 1 case of
maternal origin was unremarkable in terms of the
size or extent of the deletion, and the child
developed Wilms tumor. Transmission of 11p13
deletions by both maternal and paternal carriers of
balanced translocations has been reported, although
maternal inheritance predominates. These data, in
addition to the general predominance of paternally
derived, de novo mutations at other loci, suggested
that increased frequency of paternal deletions is
due to an increased germinal mutation rate in
males. Dao et al. (1987)
examined the karyotype and chromosome 11 genotype
of normal and tumor tissues from 13 childhood renal
tumor patients. Tumors of 8 of the 12 Wilms tumor
patients showed molecular evidence of loss of 11p
DNA sequences by somatic recombination (4 cases),
chromosome loss (2 cases), and recombination (2
cases) or chromosome loss and duplication. One
malignant rhabdoid tumor in a patient heterozygous
for multiple 11p markers did not show any
tumor-specific 11p alteration. One of the patients
had Perlman syndrome (renal hamartomas,
nephroblastomatosis, and fetal gigantism; 267000).
Lewis and Yeger
(1987) mapped the Wilms tumor region with 4
clones that were derived from the area of deletion
in 11p, together with somatic cell hybrids
containing chromosome 11 from leukemic T cells with
translocation t(11;14), from fibroblasts from a
familial aniridia patient with translocation
t(4;11), and from lymphoblasts from a patient with
Wilms tumor and deletion of 11p but no aniridia.
The following order was deduced:
centromere--CAT--T-cell break--aniridia
break--FSHB--telomere.
Porteous et al.
(1987) used chromosome-mediated gene transfer
to provide an enriched source of DNA markers for
11p. They defined 10 distinct regions of 11p, 5 of
which subdivided band 11p13. They also mapped 2
independent 11p13 translocation breakpoints to
within the smallest region of overlap defined by
WAGR deletions. The first came from a patient with
familial aniridia, and the second was found in a
neonate with the clinical features of Potter facies
and the pathologic features of genitourinary
dysplasia, with urethral and ureteral atresia and
bilateral undescended testes. Porteous
et al. (1987) raised the question of whether
Wilms tumor and genitourinary dysplasia are
alternative manifestations of mutation at the same
locus. Kumar et al.
(1987) demonstrated deletion of 11p14-p12 in a
Wilms tumor removed from a 9-month-old boy with
aniridia. Whereas morphologic transformation of
normal human cells by BK virus (BKV) and by BKV DNA
and its subgenomic fragments occurs in very low
frequency, de Ronde et al.
(1988) found that 4 individuals with various
deletions in the short arm of one chromosome 11
were unusually susceptible to morphologic
transformation. They suggested that the
susceptibility might be explained by a
'transformation suppressor' locus situated within
the deleted region. The deleted region included
that of WAGR; the 'transformation suppressor' locus
may be identical to the Wilms tumor locus. Using
the fluorescence-activated cell sorter to select a
series of somatic cell hybrids with deleted
translocated chromosome 11 segregated from its
normal homolog, Seawright
et al. (1988) analyzed these cell hybrids with
gene-specific probes and for cell-surface marker
expression to order the markers and find an SRO for
WAGR. They found that FSHB maps distal to WAGR and
CAT maps proximal to it. Two translocation
breakpoints in 11p13 (1 associated with familial
aniridia and 1 with a sporadic case of congenital
renal dysfunction resulting from urethral and
ureteral atresia) mapped within this SRO. Puissant
et al. (1988) reported a patient with WAGR and
a de novo reciprocal translocation
46,XY,t(5;11)(q11;p13). On Southern blot analysis,
the gene encoding catalase had been deleted, but
the gene encoding the beta subunit of
follicle-stimulating hormone (FSHB) was intact.
Using a range of probes for chromosome 11,
Mannens et al. (1988)
demonstrated that loss of heterozygosity in Wilms
tumors may not necessarily involve the proposed
Wilms tumor locus at 11p13 and may be limited to
11p15.5. Jeanpierre et al.
(1990) found loss of maternal alleles from the
11p15 area of the maternal chromosome in Wilms
tumor tissue and a constitutional deletion of 11p13
of the maternal chromosome. There have been other
instances in which the 11p region involved in loss
of heterozygosity (11p15) is different from the
region involved in hereditary predisposition
(11p13). See 194071.
A separate gene coding for genitourinary
dysplasia (symbolized GUD) was suggested by
Bonetta et al. (1989),
who found that the deletion breakpoint of a
translocation t(11;2)(p13;p11) in a patient with
Potter facies and genitourinary dysplasia mapped to
the same 225-kb pulsed field gel electrophoresis
fragment as did the fragment deleted in Wilms
tumor. Van Heyningen et al.
(1990) suggested that the Wilms tumor gene
itself may be responsible for abnormalities of
genitourinary development in WAGR as a pleiotropic
effect. The suggestion was based on the
observations that the tumor predisposition and the
genitourinary malformations map to precisely the
same area and that the WT candidate gene shows
expression in both the developing kidney and
gonads. See 137357
for a critique of the separate-gene hypothesis.
To localize a candidate for the Wilms tumor
gene, Rose et al.
(1990) developed a physical map of the 11p13
region by a combination of pulsed field gel
electrophoresis and irradiation-reduced somatic
cell hybrids of the Goss-Harris type. Restriction
fragments contained in 11p13 were visualized
directly using interspersed repeated DNA sequences
as hybridization probes. The Wilms tumor locus was
narrowed down to a region of less than 345 kb, and
a transcript was identified with many of the
characteristics expected for the Wilms tumor gene:
a GC-rich region mapped to the 5-prime end of a
transcription unit encoding a zinc finger protein.
Call et al. (1990)
reported further on these characteristics. The
transcription unit spanned approximately 50 kb and
encoded an mRNA approximately 3 kb long. The mRNA
was expressed predominantly in the kidney and a
subset of hematopoietic cells. The polypeptide had
features suggesting a role in transcriptional
regulation: the presence of 4 zinc finger domains
and a region rich in proline and glutamine. The
amino acid sequence of the predicted polypeptide
showed significant homology to EGR1 (128990)
and EGR2 (129010).
Gessler et al. (1990)
likewise isolated a cDNA clone derived from an RNA
highly expressed in fetal kidney which is predicted
to encode a Kruppel-like zinc finger protein that
is probably a transcription factor. Francke
(1990) commented on the significance of this
putative gene for Wilms tumor. She compared the
finding with that in retinoblastoma where a single
gene locus has been found to be responsible. She
reviewed the evidence for at least 3 genes capable
of producing Wilms tumor: one in 11p13, one in
11p15.5 (194071)
and at least one other not situated in either of
these regions (194090).
In the case of Wilms tumor, it is possible that
changes at several sites are collaborative, or
perhaps more likely that changes at several
alternative sites result in the same tumor. A third
model is that of hierarchical gene interaction. If
the function of the gene at 11p13 is to turn off
the gene at 11p15.5, then loss of 11p13 expression
would have the same effect as mutation or allele
loss at 11p15.5.
The zinc finger protein that is likely to be a
transcription factor and was isolated by Call
et al. (1990) and Gessler
et al. (1990) as the likely 'cause' of Wilms
tumor was used by Pritchard-Jones
et al. (1990) to study its role in normal
development. This was done by in situ mRNA
hybridization on sections of human embryos. The
candidate Wilms tumor gene was expressed
specifically in the condensed mesenchyme, renal
vesicle, and glomerular epithelium of the
developing kidney, in the related mesonephric
glomeruli, and in cells approximating these
structures in tumors. The other main sites of
expression were the genital ridge, fetal gonad, and
mesothelium. This was interpreted as indicating
that the anomalies of the urinary tract and
genitalia, which are frequent in both sporadic and
syndrome-associated Wilms tumors, are a pleiotropic
effect of the WT1 gene. Huff
et al. (1991) made observations that appeared
to differentiate between WT33 and LK15, 2 similar
candidate Wilms tumor cDNA clones that were
identified on the basis of their expression in
fetal kidney and their location within the smallest
region of overlap of somatic 11p13 deletions in
Wilms tumors. However, Gessler
(1991) concluded that LK15 and WT33 are
identical, with differences due to alternative
splicing at 2 exons. Huff et
al. (1991) reported a patient with bilateral
Wilms tumor who was heterozygous for a small
germinal mutation within the WT1 gene (as
identified by the WT33 clone). DNA from both tumors
was homozygous for this intragenic deletion, which
was predicted to encode a protein truncated by 180
amino acids.
Haber et al. (1990)
described a sporadic, unilateral Wilms tumor in
which 1 allele of the WT1 candidate gene contained
a 25-bp deletion spanning an exon-intron junction
and leading to aberrant mRNA splicing and loss of 1
of the 4 zinc finger consensus domains in the
protein. The mutation was absent in the affected
person's germline, consistent with the somatic
inactivation of a tumor suppressor gene. In
addition to the intragenic deletion affecting 1
allele, loss of heterozygosity at loci along the
entire chromosome 11 indicated an earlier
chromosomal nondisjunction and reduplication.
Haber et al. (1992)
presented evidence that this mutation of the WT1
gene behaves as a dominant negative, suppressing
the function of the wildtype protein by a
trans-dominant mechanism. They suspected this
because the mutated allele was found to be
coexpressed with the wildtype allele in a sporadic
Wilms tumor. They therefore tested the ability of
this mutant WT1 allele, containing an in-frame
deletion within the DNA-binding domain, to
transform primary baby rat kidney cells. The mutant
WT1 gene was found to cooperate with the adenoviral
E1A gene in transforming baby rat kidney cells. The
wildtype WT1 gene in all of its alternatively
spliced forms neither suppressed E1A-induced focus
formation nor cooperated with E1A. Hastie
(1992) also reviewed the evidence showing that
mutations in the WT1 gene behave as dominant
negatives, specifically in relation to causation of
the Denys-Drash syndrome (DDS). This is proof that
a tumor-suppressor gene plays a crucial role in
normal genitourinary development. It seems quite
clear that there is not a separate gene for the 'G'
part of the WAGR syndrome although there is a
separate gene for aniridia and almost certainly for
mental retardation. Remarkably, 12 out of 25
patients from a total of 4 studies had the
arg394-to-trp mutation (194070.0003)
in heterozygous form as the cause of the
Denys-Drash syndrome. One reason for the
preponderance of this mutation is that it
represents a C-to-T transition at a CpG dimer. The
same can be said for the arg-to-his change
(194070.0004).
This, however, appeared to be only part of the
story since there are other equally vulnerable
sites; Hastie (1992)
suggested that the zinc fingers carrying these 2
mutations may play a particularly important role in
establishing stable binding.
Mutations causing the Denys-Drash syndrome are
clustered in the zinc finger encoding exons,
particularly the exons encoding ZF2 and ZF3.
Little et al. (1993)
concluded that WT mutations resulting in the
Denys-Drash syndrome may operate in a
dominant-negative fashion; they observed an
arg362-to-ter mutation predicted to result in a
protein product lacking zinc fingers 2, 3 and 4,
and therefore presumably incapable of binding DNA.
Little et al. (1995)
found WT1 fusion constructs containing the
different classes of DDS-causing mutations. They
demonstrated that the DDS mutations, indeed,
disrupt DNA binding. They interpreted this as
compatible with a dominant-negative mode of action,
perhaps through dimerization between different WT1
isoforms. Little et al.
(1995) noted that another mechanism by which
the loss of DNA-binding could elicit the DDS
phenotype would be a disturbed isoform dosage
balance.
Nordenskjold et al.
(1995) screened 27 cases of 46,XY females with
gonadal dysgenesis who had previously been screened
for and found not to carry SRY gene mutations
(480000)
to determine whether isolated gonadal dysgenesis
might be due to WT mutations. Using denaturing
gradient gel electrophoresis, they found a
heterozygous point mutation in exon 8 in 1 of these
patients: arg366-to-his, which had previously been
described in a case of Denys-Drash syndrome
(194070.0004).
Reevaluation of the clinical data confirmed the
diagnosis of Drash syndrome. Based on these
results, Nordenskjold et al.
(1995) concluded that isolated gonadal
dysgenesis is not caused by mutations in the WT1
gene.
Ton et al. (1991)
demonstrated that the smallest region of overlap
between deletions causing Wilms tumor was a 16-kb
segment of DNA encompassing one or more of the
5-prime exons of the zinc finger gene located on
11p13, together with an associated CpG island. This
supported the authenticity of the zinc finger gene
as the disease locus. Kakati
et al. (1991) described a family in which a son
had bilateral WT and an extra ring chromosome in
the lymphocytes and in kidney tissue. The size of
the ring varied considerably from cell to cell. A
daughter had unilateral WT and an abnormal clone
containing a small ring chromosome in
PHA-stimulated and EBV-transformed lymphocytes. The
mother, who was unaffected, had a karyotype similar
to that of the daughter with WT. Kakati
et al. (1991) hypothesized that the son's large
ring chromosome was an amplified form of the small
ring inherited from the mother. Chromosome 11 was
cytogenetically normal in all cells examined in the
affected children and the unaffected mother.
The WT1 gene comprises 10 exons, encoding a
complex pattern of mRNA species. Four distinct
transcripts are expressed, reflecting the presence
or absence of 2 alternative splices (Haber
et al., 1991). The conservation in structure
and relative levels of the 4 WT1 mRNA species
suggests that each encoded polypeptide makes a
significant contribution to normal gene function.
The control of cellular proliferation and
differentiation exerted by the WT1 gene products
may involve interactions between the 4 polypeptides
with distinct targets and functions. Using
polyclonal antibodies, Dressler
and Douglass (1992) detected high levels of
Pax-2 (PAX2) expression in the epithelial cells of
human Wilms tumors. In the mouse they showed by
immunocytochemistry that expression of the Pax-2
gene was localized to the nuclei of condensing
mesenchyme cells and their epithelial derivatives
in the developing kidney. The data suggested that
Pax-2 is a transcription factor that is active
during the mesenchyme-to-epithelium transition in
early kidney development and in Wilms tumor. Pax-2
is a member of the family of genes identified in
the mouse on the basis of a common protein coding
domain, the paired-box, first described in the
Drosophila segmentation genes 'paired' and
'gooseberry.' The Pax genes are expressed during
embryogenesis in a tissue-restricted manner. The
gene mutant in Waardenburg syndrome (193500)
is the human homolog of the Pax-3 gene and the gene
mutant in aniridia (106210)
is the human homolog of the Pax-6 gene. To
facilitate the search for small deletions and point
mutations in the WT1 gene, Gessler
et al. (1992) established the genomic
organization of the gene and determined the
sequence of all 10 exons and the flanking intron
DNA. The pattern of alternative splicing in 2
regions was characterized in detail.
In 2 cases in which a Wilms tumor contained a
somatic WT1 mutation, Park
et al. (1993) found that nephrogenic rests in
the same kidneys had the identical mutation. Thus,
nephrogenic rests and Wilms tumor are
topographically distinct lesions that are clonally
derived from an early renal stem cell. Inactivation
of WT1 appears to be an early genetic event that
can lead to the formation of nephrogenic rests,
enhancing the probability that additional genetic
hits will lead to Wilms tumor. In the case of both
P53 (191170)
and retinoblastoma (180200),
characterization of the tumor suppressor genes was
provided by the dramatic growth-suppressing
properties when the genes were reintroduced into
cells containing inactivated endogenous genes.
Similar studies in Wilms tumors had been
complicated by the existence of multiple genetic
loci implicated in different subsets of tumors and
by the unavailability of appropriate target cell
lines. To obtain an appropriate cell line for
studying WT1 function, Haber
et al. (1993) inoculated minced human Wilms
tumors subcutaneously into nude mice and then
adapted the tumor explants to growth in vitro. They
found that 1 cell line could be propagated
indefinitely in tissue culture without loss of
tumorigenic potential. Transfection of each of 4
wildtype WT1 isoforms suppressed the growth of
these cells. The endogenous WT1 transcript in these
cells was devoid of exon 2 sequences, a splicing
alteration that was also detected in varying
amounts in all Wilms tumors tested but not in
normal kidney. Production of this abnormal
transcript, which encodes a functionally altered
protein, may represent a distinct mechanism for
inactivating WT1 in Wilms tumors.
Varanasi et al.
(1994) analyzed the structural integrity of the
entire WT1 gene in 98 sporadic Wilms tumors. By
PCR-SSCP, they found that mutations in the WT1 gene
are rare, occurring in only 6 tumors analyzed. In 1
sample, 2 independent intragenic mutations
inactivated both WT1 alleles, providing a singular
example of 2 different somatic alterations
restricted to the WT1 gene. The data, together with
the previously ascertained occurrence of large
deletions/insertions in WT1, defined the frequency
at which the WT1 gene is altered in sporadic
tumors.
By gene targeting in embryonic stem cells,
Kreidberg et al. (1993)
introduced a mutation into the murine WT1 tumor
suppressor gene. The mutation resulted in embryonic
lethality in homozygotes, and examination of mutant
embryos demonstrated a failure of kidney and gonad
development. Specifically, at day 11 of gestation,
the cells of the metanephric blastema underwent
apoptosis, the ureteric bud failed to grow out from
the Wolffian duct, and the inductive events that
lead to formation of the metanephric kidney did not
occur. In addition, the mutation caused abnormal
development of the mesothelium, heart, and lungs.
The results established a crucial role for WT1 in
early urogenital development.
Gerald et al. (1995)
reported the first example of a specific tumor
associated with consistent translocation involving
WT1. Desmoplastic small round cell tumor (DSRCT) is
associated with a recurrent chromosomal
translocation, t(11;22)(p13;q12). DSRCT is
characterized by a predilection for young males,
abdominal serosal involvement, poor prognosis, and
a primitive histologic appearance. Gerald
et al. (1995) found that the chromosome
translocation breakpoints involved the intron
between WT1 exons 7 and 8 and the intron between
EWS (133450)
exons 7 and 8. Chimeric transcripts corresponding
to the fusion gene were detected in 4 of 6 cases of
DSRCT. Analyses of these transcripts showed an
in-frame fusion of RNA encoding the amino-terminal
domain of EWS to both alternatively spliced forms
of the last 3 zinc fingers of the DNA-binding
domain of WT1. The chimeric products were predicted
to modulate transcription at WT1 target sites and
contribute to development of this unique tumor.
WT1 encodes a zinc finger protein expressed as
distinct isoforms. Both constitutional and somatic
mutations disrupting the DNA-binding domain of WT1
result in a potentially dominant-negative
phenotype. In generating inducible cell lines
expressing wildtype isoforms of WT1 as well as WT1
mutants, Englert et al.
(1995) observed dramatic differences in the
subnuclear localization of the induced proteins.
The WT1 isoform that binds with high affinity to a
defined DNA target, WT1(-KTS), was diffusely
localized throughout the nucleus. In contrast,
expression of an alternative splicing variant with
reduced DNA binding affinity, WT1(+KTS), or WT1
mutants with a disrupted zinc finger domain
resulted in a speckled pattern of expression within
the nucleus. Though similar in appearance, the
localization of WT1 variants to subnuclear clusters
was clearly distinct from that of the essential
splicing factor SC35, suggesting that WT1 is not
directly involved in pre-mRNA splicing.
Localization to subnuclear clusters required the M
terminus of WT1 and coexpression of a truncated WT1
mutant and wildtype WT1(-KTS) resulted in a
physical association, the redistribution of
WT1(-KTS) from a diffuse to a speckled pattern, and
the inhibition of its transactivational activity.
These observations suggested to the authors that
different WT1 isoforms and WT1 mutants have
distinct subnuclear compartments. Dominant-negative
WT1 proteins physically associate with wildtype WT1
in vivo and may result in its sequestration within
subnuclear structures.
Products of the steroidogenic factor-1 (SF1;
184757)
and WT1 genes are essential for mammalian
gonadogenesis prior to sexual differentiation. In
males, SF1 participates in sexual development by
regulating expression of the polypeptide hormone
Mullerian inhibiting substance (MIS; 600957).
Nachtigal et al. (1998)
showed that WT1-KTS isoforms associate and
synergize with SF1 to promote MIS expression. In
contrast, WT1 missense mutations, associated with
male pseudohermaphroditism in Denys-Drash syndrome,
fail to synergize with SF1. Additionally, the
X-linked, candidate dosage-sensitive sex-reversal
(DSS; 300018)
gene, DAX1 (300200),
antagonizes synergy between SF1 and WT1, most
likely through a direct interaction with SF1.
Nachtigal et al. (1998)
proposed that WT1 and DAX1 functionally oppose each
other in testis development by modulating
SF1-mediated transactivation.
Little and Wells
(1997) pointed out that only 5% of sporadic
Wilms tumors have intragenic WT1 mutations, but
more than 90% of patients with the Denys-Drash
syndrome carry constitutional intragenic WT1
mutations. WT mutations have also been reported in
juvenile granulosa-cell tumor, non-asbestos-related
mesothelioma Park et al.
(1993), desmoplastic small round cell tumor,
and acute myeloid leukemia.
Schumacher et al.
(1997) identified 19 hemizygous WT1 gene
mutations/deletions in tissue samples from 64
patients. The histology of the tumors with
mutations was stromal-predominant in 15, triphasic
in 3, blastemal-predominant in 1, and unknown in 2
cases. Among 21 patients with stromal-predominant
tumors, 15 had WT1 mutations and 10 of these were
present in the germline. Of the patients with
germline alterations, 6 had associated
genitourinary (GU) tract malformations and a
unilateral tumor, 2 had a bilateral tumor and
normal GU tracts, and 2 had a unilateral tumor and
normal GU tracts. Three mutations were
tumor-specific and were found in patients with
unilateral tumors without genital tract
abnormalities. These data demonstrated the
correlation of WT1 mutations with
stromal-predominant histology, suggesting that a
germline mutation in WT1 predisposes to the
development of tumors with this histology. Twelve
mutations were nonsense mutations resulting in
truncation at different positions in the WT1
protein, and only 2 were missense mutations. Of the
stromal-predominant tumors, 67% showed loss of
heterozygosity, and in 1 tumor a different somatic
mutation in addition to the germline mutation was
identified. Thus, in a large proportion of a
histopathologically distinct subset of Wilms
tumors, the classic 2-hit inactivation model, with
loss of a functional WT1 protein, is the underlying
cause of tumor development.
Little et al. (1992)
demonstrated that each parental allele of WT1 is
equivalently expressed in normal fetal kidneys and
Wilms tumors. On the other hand, Jinno
et al. (1994) identified imprinting of WT1,
with maternal expression in about half of preterm
placental villus and fetal brain tissue. Further
extensive studies showed that maternal monoallelic
expression was observed in 39% of the samples,
while the expression in other samples was
biallelic. Mitsuya et al.
(1997) studied the allele-specific expression
of WT1 as well as of IGF2 and H19 in fibroblasts
and lymphocytes. The expression profiles of IGF2
and H19 were constant and consistent with those in
other tissues. The unexpected finding was paternal
or biallelic expression of WT1 in fibroblasts and
lymphocytes. This, together with the previous
findings of maternal or biallelic expression in
placenta and brain, suggested that the
allele-specific regulatory system of WT1 is unique
and may be controlled by a putative tissue- and
individual-specific modifier.
Miyagawa et al.
(1998) focused on the ectopic formation of
skeletal muscle in Wilms tumors. They presented
evidence supporting a negative regulatory role for
WT1 in myogenesis. Their findings suggested that
the metanephric-mesenchymal stem cells of the
kidney may have the capacity to differentiate into
skeletal muscle cells as well as epithelial cells.
Normally, the expression of WT1 appears to prevent
this ectopic differentiation program from being
activated. In vitro studies suggested that WT1 may
play a direct role in suppressing the formation of
skeletal muscle.
Jeanpierre et al.
(1998) identified WT1 mutations in patients
with isolated diffuse mesangial sclerosis
(256370),
i.e., patients without pseudohermaphroditism and/or
Wilms tumor which represent the other features of
the Denys-Drash syndrome (DDS; 194080).
In 4 of 10 patients, they found heterozygous
mutations in the WT1 gene. Two mutations were
different from those described in DDS patients. An
analysis of genotype/phenotype correlation, on the
basis of a WT1 mutation database of 84 germline
mutations, demonstrated an association between
mutations in exons 8 and 9 and DMS; among patients
with DMS, a higher frequency of exon 8 mutations
among 46,XY patients with female phenotype than
among 46,XY patients with sexual ambiguity or male
phenotype; and statistically significant evidence
that mutations in exons 8 and 9 preferentially
affect amino acids with different functions.
Beckwith (1998)
provided useful data on the age at diagnosis of the
first Wilms tumor in cases of syndrome-associated
WT. Among 121 cases of Wiedemann-Beckwith syndrome,
96% were diagnosed by age 8 years; the oldest WBS
patient had WT detected at 10 years, 2 months.
Among 203 patients with hemihyperplasia, 94% were
detected by age 8; the oldest HH patient had WT
detected at 12 years, 4 months. Among 61 WAGR
patients, Wilms tumor was detected in 98% by age 6
years; the oldest WAGR patient had WT detected at 7
years, 3 months. Among 52 patients with Denys-Drash
syndrome, WT was detected in 96% by age 5 years;
the oldest DDS patient had WT detected at 6 years
of age.
ALLELIC
VARIANTS
-
-
.0001 WAGR
SYNDROME [WT1, 17-BP DEL, EX4]
Pelletier et al.
(1991) reported constitutional mutations
within the WT1 genes of 2 persons with a
combination of Wilms tumor and genital
abnormalities. They interpreted the findings as
evidence of a role for a recessive oncogene in
mammalian development. One patient (P.G.) had
bilateral Wilms tumor, hypospadias, and
undescended left testis. A small deletion in
exon 4 was observed in a PCR product from
chromosome 11, which was retained in P.G.'s
first Wilms tumor. Specimens of a second tumor
revealed both a normal PCR product of about 130
bp and the deleted product of 110 bp. In the
tumor tissue, only the 110-bp fragment was
found. Pelletier et al.
(1991) concluded that in both tumors
reduction to homozygosity for the WT1 allele
containing a small deletion in exon 4
contributed to tumor formation. Sequence
analysis of the abnormal allele showed a 17-bp
deletion predicted to cause premature
polypeptide chain termination in the exon. The
deletion occurred between 2 copies of the
pentanucleotide sequence TGACA. P.G.'s germline
mutation appeared to be the consequence of
either polymerase skipping during DNA
replication or an unequal crossover event.
-
-
.0002 WAGR
SYNDROME [WT1, 1-BP DEL, EX6, FS]
In patient T.S., born with hypospadias and
bilateral cryptorchidism and later developing
Wilms tumor, Pelletier et
al. (1991) found, by single strand
conformation polymorphism (SSCP) analysis, a
difference in the mobility pattern of exon 6 due
to a single nucleotide deletion, a guanosine, in
exon 6, which was predicted to cause early
termination of translation. The father had been
treated successfully for Wilms tumor in 1959.
This was probably the first documentation of a
transmitted WT1 mutation in familial Wilms
tumor.
-
-
.0003
DENYS-DRASH SYNDROME [WT1,
ARG394TRP]
Denys-Drash syndrome is a rare human
condition in which severe urogenital aberrations
result in renal failure, pseudohermaphroditism,
and Wilms tumor. In 10 cases of the syndrome,
Pelletier et al.
(1991) found point mutations in the zinc
finger domains of one WT1 gene. Nine of these
mutations were found within exon 9 (zinc finger
III); the remaining mutation was in exon 8 (zinc
finger II). These mutations directly affected
DNA sequence recognition. In 2 families
analyzed, the mutations were shown to arise de
novo. Wilms tumors from 3 individuals and 1
juvenile granulosa cell tumor demonstrated
reduction to homozygosity for the mutated WT1
allele. In 7 of the 10 cases, the change was a
substitution of tryptophan for arginine at codon
394. Several of the patients with a 46,XY
karyotype had ambiguous or female external
genitalia with dysgenic or streak gonads. All
the patients had nephropathy, which was commonly
described as focal or diffuse mesangial
sclerosis. Two patients had gonadoblastoma, and
one of these also had juvenile granulosa cell
tumor. (Although this syndrome had commonly been
referred to as Drash syndrome (194080),
Pelletier et al.
(1991) referred to it as the Denys-Drash
syndrome since the constellation of anomalies
was first described in the French literature by
Denys et al. (1967).)
In a 46,XY individual with ambiguous genitalia,
rudimentary uterus, fimbriated fallopian tubes,
and streak gonads, who was described in greater
detail by McCoy et al.
(1983), Bruening et
al. (1992) demonstrated a point mutation
within exon 9, which converted arginine-394 to
tryptophan. The patient's mother did not carry
the mutation. Baird et al.
(1992) found this mutation, a C-to-T
transition at nucleotide 1180, in 3 of 8
patients with the Denys-Drash syndrome.
Coppes et al. (1992)
found the arg394-to-trp (exon 9) mutation in 2
of 3 patients with the Denys-Drash syndrome.
Unlike patients in previous reports, one of the
patients inherited the mutant allele from his
phenotypically unaffected father. The father had
no abnormalities and, in particular, he had
bilaterally descended testes of normal volume
and a normal penis without hypospadias. He had
donated his kidney for transplantation to his
son with Denys-Drash syndrome. Little
et al. (1993) reported the same mutation.
-
-
.0004
DENYS-DRASH SYNDROME [WT1,
ARG366HIS]
One of 10 patients studied by Pelletier
et al. (1991) had a germline mutation
resulting in substitution of histidine for
arginine at codon 366. The same mutation was
observed by Baird et al.
(1992).
-
-
.0005
DENYS-DRASH SYNDROME [WT1,
ASP396GLY]
One of the 10 patients studied by Pelletier
et al. (1991) had a germline mutation in the
WT1 gene leading to substitution of glycine for
aspartic acid at codon 396.
-
-
.0006
DENYS-DRASH SYNDROME [WT1,
ASP396ASN]
One of the 10 patients studied by Pelletier
et al. (1991) had a germline mutation of the
WT1 gene resulting in substitution of asparagine
for aspartic acid at codon 396. Baird
et al. (1992) found the same mutation, a
G-to-A transition at nucleotide 1186, in 1 of 8
patients with Denys-Drash syndrome. The
asp396-to-asn mutation was also reported by
Little et al. (1993);
a G-to-A transition affecting ZF3 was present in
heterozygous state constitutionally and was
homozygous in the bilateral Wilms tumor.
-
-
.0007
DENYS-DRASH SYNDROME [WT1,
ARG394PRO]
In a phenotypic female with a 46,XY
chromosome constitution and nephropathy with
Wilms tumor, Bruening et
al. (1992) identified a guanine to cytosine
transversion in exon 9, converting arginine-394
to proline. Genomic DNA from this patient (J.K.)
was available only from a Wilms tumor specimen
embedded in paraffin. Bruening
et al. (1992) suspected that, like other
patients with Denys-Drash syndrome (Pelletier
et al., 1991), J.K. was germline hemizygous
for this mutation.
-
-
.0008
DENYS-DRASH SYNDROME [WT1,
CYS330TYR]
In a patient (K.J.) with Denys-Drash
syndrome, Bruening et al.
(1992) identified a point mutation within
exon 7 (zinc finger I) converting cysteine-330
to tyrosine. The patient had a 46,XX karyotype
and mild clitoromegaly. Nephropathy was present
and both kidneys showed extensive intralobar
persistent renal blastema but no overt Wilms
tumor.
-
-
.0009
DENYS-DRASH SYNDROME [WT1, IVS9DS, G-A,
+5]
In C.S., a patient with renal failure due to
glomerular sclerosis associated with female
external genitalia and a 46,XY karyotype,
Bruening et al.
(1992) discovered a mutation by SSCP which
was found to represent a guanine-to-adenine
transition at position +5 of the splice donor
site within intron 9. It appeared that the
mutation affected the alternative splice site
selection at exon 9. The various WT1 splice
forms have a similar relative abundance in
different mouse and human tissues as well as in
different Wilms tumors. These splice forms are
referred to as A, which lacks both alternatively
spliced exons; B, which contains the first
alternatively spliced exon; C, which contains
the second alternatively spliced exon; and D,
which contains both alternatively chosen exons.
Several isoforms may have different functions.
-
-
.0010 WILMS
TUMOR [WT1, ARG-TER, ZF3]
In an infant who presented with simultaneous
bilateral Wilms tumor at the age of 11 months,
Little et al. (1992)
found a point mutation at a CpG dinucleotide in
zinc finger 3, changing a C to a T at nucleotide
350 and resulting in an arginine becoming a stop
codon. The mutation was detected
constitutionally in both tumors of the patient.
It was present in heterozygous state in 1 tumor
and in somatic cells, whereas due to
hemizygosity, the other tumor carried only the
mutant allele. Neither parent carried the
mutation.
-
-
.0011 WILMS
TUMOR [WT1, ARG-CYS, ZF2]
In a 3-year-old child with unilateral
sporadic Wilms tumor and no family history of
renal neoplasia or associated anomalies or
cytogenetic abnormalities, Little
et al. (1992) found a C-to-T transversion at
nucleotide 339 of zinc finger 2, resulting in an
arginine to cysteine amino acid change. The
mutation was present in only 1 allele of the
tumor and was not present constitutionally or in
either of the parents. Furthermore, it was not
found in any of 34 normal, unrelated Caucasians.
-
-
.0012
DENYS-DRASH SYNDROME [WT1,
HIS377TYR]
In constitutional DNA from a patient with
Denys-Drash syndrome, Coppes
et al. (1992) found a C-to-T transition of
nucleotide 1129 converting amino acid residue
his377 to tyr. The change occurred in exon
8.
-
-
.0013
DENYS-DRASH SYNDROME [WT1,
CYS360GLY]
In a patient with unilateral Wilms tumor and
'Drash' nephropathy, Little
et al. (1993) described a T-to-G
transversion converting codon 360 from cysteine
to glycine. The mutation was heterozygous in
both the constitution and the tumor.
-
-
.0014
DENYS-DRASH SYNDROME [WT1,
ARG362TER]
In a 46,XY patient with micropenis and
cryptorchidism, bilateral Wilms tumor, and
'Drash' nephropathy, Little
et al. (1993) described a C-to-T transition
converting codon 362 from arginine to a stop
codon. It was present in heterozygous state in
the constitution and homozygous state in the
tumors. Since the mutation affected ZF2,
resulting in a truncated protein interfering
with DNA binding, Little
et al. (1993) suggested that missense
mutations operate by a dominant-negative
mechanism.
-
-
.0015
DENYS-DRASH SYNDROME [WT1,
HIS373GLN]
In a 46,XY patient with hypospadias and
'Drash' nephropathy, Little
et al. (1993) described a C-to-G
transversion converting codon 373 in ZF2 from
histidine to glutamine.
-
-
.0016
MESOTHELIOMA [WT1, SER273GLY]
Park et al. (1993)
showed that the WT1 gene, in addition to being
expressed in tissues of the genitourinary
system, is also expressed at high levels in many
supportive structures of mesodermal origin in
the mouse. Furthermore, they described a case of
adult human mesothelioma that contained a
homozygous A-to-G transition resulting in a
serine to glycine substitution at codon 273.
Normal tissue from the patient showed no
evidence of this mutation, indicating that it
was absent from the germline and arose as a
somatic mutation within the tumor. Mesothelioma
is a tumor derived from the peritoneal lining.
The particular tumor studied was of the rare
multicystic type which is not metastatic and has
been classified as a hamartoma or a
developmental abnormality of borderline
malignancy (Salazar et
al., 1972). Unlike most mesotheliomas,
multicystic tumors are not associated with a
history of asbestos exposure. Park
et al. (1993) screened 32 specimens of
asbestos-related mesothelioma and found no WT1
mutations. The ser273-to-gly mutation was the
first reported outside the zinc finger domain
that leads to an amino acid substitution rather
than a termination codon. Codon 273 is highly
conserved across species. Whereas wildtype WT1
represses transcription from the early growth
response-1 (EGR1; 128990)
promoter, following cotransfection into NIH 3T3
cells, Park et al.
(1993) found that insertion of the
ser273-to-gly mutation resulted in a WT1 protein
that activated transcription from the EGR1
promoter.
-
-
.0017 WILMS
TUMOR, FAMILIAL [WT1, ARG362TER]
Kaplinsky et al.
(1996) identified a nonsense mutation in the
WTN gene in the Wilms tumor of 3 sisters who had
the same father but 2 different mothers: a
C-to-T transition at nucleotide 1084 (relative
to the A of the ATG initiation codon) of the WT1
gene resulted in an arg362-to-ter substitution
within zinc finger II. The mutation was
predicted to result in the production of a
truncated WT1 polypeptide unable to bind DNA.
Two other sibs, both male, were unaffected. Two
of the sisters had unilateral Wilms tumor, 1 had
bilateral disease. The father, although a
carrier, had never developed WT. Kaplinsky
et al. (1996) commented that this may be due
to incomplete penetrance, which is not gender
related. Alternatively, the father could be
mosaic for the WT1 mutation, such that mutant
cells had not substantially contributed to
development of the urogenital system. A third
possibility is that genomic imprinting of the
mutated WT1 allele is responsible for masking
its expression in the male carrier. In the
proband, analysis of DNA from a Wilms tumor
revealed loss of heterozygosity with retention
of 1 set of conformers present in the proband
and the father. This pattern is classical for
tumor suppressor gene analysis and suggested the
unmasking of a recessive mutation by loss of the
wildtype allele.
-
-
.0018 FRASIER
SYNDROME [WT1, IVS9DS, C-T, +4]
Frasier syndrome (136680)
is a rare disorder defined by male
pseudohermaphroditism and progressive
glomerulopathy (Frasier
et al., 1964; Haning
et al., 1985; Kinberg
et al., 1987). Patients present with normal
female external genitalia, streak gonads, and XY
karyotype, and frequently develop gonadoblastoma
(Blanchet et al.,
1977). Glomerular symptoms consist of
childhood proteinuria and nephrotic syndrome,
characterized by nonspecific focal and segmental
glomerular sclerosis, progressing to end-stage
renal failure in adolescence or early adulthood.
Wilms tumor is not a feature of the syndrome. In
contrast with Frasier syndrome, most individuals
with Denys-Drash syndrome (194080)
have ambiguous genitalia or a female phenotype,
an XY karyotype, and dysgenetic gonads. Renal
symptoms are characterized by diffuse mesangial
sclerosis, usually before the age of 1 year, and
the patients frequently develop Wilms tumor.
Alternative splicing of WT1 generates 4
isoforms: the fifth exon may or may not be
present, and an alternative splice site in
intron 9 allows the addition of 3 amino acids
(lys-thr-ser, or KTS) between the third and
fourth zinc fingers of the WT1 protein
(Haber et al., 1991).
Barbaux et al. (1997)
demonstrated that Frasier syndrome was caused by
a mutation in the donor splice site in intron 9
of WT1, with the predicted loss of the so-called
+KTS isoform. Examination of WT1 transcripts
showed a diminution of the +KTS/-KTS isoform
ratio in patients with Frasier syndrome. Three
unrelated patients presented with persistent
proteinuria between the ages of 2 and 6 years
and subsequently developed nephrotic syndrome
that progressed to end-stage renal failure
between 9 and 35 years of age. Renal biopsies
performed before the onset of renal
insufficiency showed minimal nonspecific
glomerular changes in 1 patient and focal and
segmental glomerular sclerosis in the other 2
patients. All 3 patients underwent successful
kidney transplantation without recurrence of the
nephrotic syndrome. Evaluation of primary
amenorrhea in these 3 females with normal female
phenotype led to diagnosis of 46,XY gonadal
dysgenesis. One of the 3 patients developed
gonadoblastoma, which was diagnosed when she was
19; no recurrence was observed after surgical
treatment. The other 2 patients underwent
bilateral surgical gonadectomy. Two of 3
patients were found to carry the C-to-T
transition at position +4 of intron 9 in 1
allele. This nucleotide substitution was not
detected in the DNA from either parent,
indicating a de novo mutation. A third patient
was found to have a mutation in intron 9 at
position +6, substituting a thymidine for an
adenine (194070.0019).
A screen of the SRY gene (480000)
had failed to detect mutations in any of the 3
patients.
Klamt et al.
(1998) reported 3 cases of Frasier syndrome
and the IVS9DS+4C-T mutation.
Barbosa et al.
(1999) stated that 18 patients with Frasier
syndrome had been described, all with
heterozygous point mutations affecting the donor
splice site of intron 9 of WT1; none had
presented with Wilms tumor. They described 2
patients with Frasier syndrome and the
IVS9DS+4C-T mutation; one of these patients also
had Wilms tumor. The mutation was detected in
both peripheral blood and in tumor-derived DNA
of the patient with Frasier syndrome and Wilms
tumor. The congenital anomalies in these 2
patients were the same as in other cases of
Frasier syndrome: female external genitalia, in
spite of a 46,XY karyotype, and streak gonads.
The nephroblastoma in the patient with Wilms
tumor had been diagnosed at the age of 3 years.
The possibility that the patient actually
represented a case of Denys-Drash syndrome was
rejected because of normal histology of the
kidney removed at age 3; the late onset of
proteinuria; the slow progression of
nephropathy, once developed; and the presence of
a complete female phenotype with dysgenetic
gonads, typical of Frasier syndrome. Thus this
is the only one of 20 patients carrying
mutations within splice site 2 of exon 9 of the
WT1 gene who developed Wilms tumor in
association with the features of Frasier
syndrome.
-
-
.0019 FRASIER
SYNDROME [WT1, IVS9DS, A-T, +6]
See 194070.0018
and Barbaux et al.
(1997).
-
-
.0020 FRASIER
SYNDROME [WT1, IVS9DS, G-A, +5]
Klamt et al.
(1998) described 6 cases of an IVS9DS+5G-A
mutation in the WT1 gene. Merging of mutational
data from 18 cases demonstrated a striking bias:
15 of the 18 cases showed either the +4C-T
(194070.0018)
or the +5G-A mutations. This mutational hotspot
probably results from the potential to deaminate
5-methylcytosine at the +4/+5 CpG dinucleotide.
Klamt et al. (1998)
showed that disruption of alternative splicing
at the exon 9 donor splice site prevents
synthesis of the usually more abundant WT1 +KTS
isoform from the mutant allele. In contrast to
Denys-Drash syndrome, no mutant protein is
produced. The splice mutation leads to an
imbalance of WT1 isoforms in vivo, as detected
by RT-PCR on streak gonadal tissue. Thus, WT1
isoforms must have different functions, and the
pathology of Frasier syndrome suggests that
gonadal development may be particularly
sensitive to imbalance or relative
underrepresentation of the WT1 +KTS isoform.
(The +KTS isoform has 3 additional amino acids,
lys-thr-ser, between the third and fourth zinc
fingers of the WT1 protein (Haber
et al., 1991).)
-
-
.0021
MESANGIAL SCLEROSIS, ISOLATED DIFFUSE [WT1,
HIS377TYR]
In a 46,XX female with normal external
genitalia and normal puberty associated with
isolated diffuse mesangial sclerosis (256370),
Jeanpierre et al.
(1998) demonstrated an 1129C-T transition in
exon 8 of the WT1 gene that produced an
his377-to-tyr (H377Y) amino acid substitution.
The first symptoms occurred at the age of 6
months; end-stage renal failure was present by
age 3 years and 10 months.
-
-
.0022
MESANGIAL SCLEROSIS, ISOLATED DIFFUSE [WT1,
PHE383LEU]
In a male patient with normal external
genitalia and normal puberty associated with
isolated diffuse mesangial sclerosis (256370),
Jeanpierre et al.
(1998) found an 1147T-C transition in exon
9, leading to an phe383-to-leu (F383L) amino
acid substitution in the WT1 protein.
-
-
.0023
MESANGIAL SCLEROSIS, ISOLATED DIFFUSE [WT1,
ASP396ASN ]
In a 46,XX female with normal external
genitalia and DMS (256370),
Jeanpierre et al.
(1998) found an 1186G-A transition in exon 9
of the WT1 gene, leading to a asp396-to-asn
(D396N) amino acid substitution in the WT1
protein.
-
SEE ALSO
- Babaian et al.
(1980) ; Cordero et
al. (1980) ; DiGeorge
and Harley (1966) ; Francke
et al. (1979) ; Fraumeni
and Glass (1968) ; Huerre
et al. (1983) ; Juberg
et al. (1975) ; Kaufman
et al. (1973) ; Knudson
and Strong (1975) ; Kolata
(1980) ; Kontras and
Newton (1974) ; Ladda
et al. (1974) ; Neidhardt
(1972) ; Pelletier et
al. (1991) ; Slater
and de Kraker (1982) ; Turleau
et al. (1984) ; Yunis
and Ramsay (1980)
REFERENCES
- 1. Anderson, S. R.;
Geertinger, P.; Larsen, H.-W.; Mikkelsen, M.;
Parving, A.; Vestermark, S.; Warburg, M. :
- Aniridia, cataract and
gonadoblastoma in a mentally retarded girl with
deletion of chromosome 11: a clinicopathological
case report. Ophthalmologica
176: 171-177, 1978.
- 2. Babaian, R. J.;
Skinner, D. G.; Waisman, J. :
- Wilms' tumor in the adult patient:
diagnosis, management, and review of the world
medical literature. Cancer 45:
1713-1719, 1980.
PubMed ID : 6245783
- 3. Baird, P. N.;
Santos, A.; Groves, N.; Jadresic, L.; Cowell, J.
K. :
- Constitutional mutations in the WT1
gene in patients with Denys-Drash
syndrome. Hum. Molec. Genet.
1: 301-305, 1992.
PubMed ID : 1338906
- 4. Barbaux, S.;
Niaudet, P.; Gubler, M.-C.; Grunfeld, J.-P.;
Jaubert, F.; Kuttenn, F.; Fekete, C. N.;
Souleyreau-Therville, N.; Thibaud, E.; Fellous,
M.; McElreavey, K. :
- Donor splice-site mutations in WT1
are responsible for Frasier syndrome.
Nature Genet. 17: 467-470, 1997.
PubMed ID : 9398852
- 5. Barbosa, A. S.;
Hadjiathanasiou, C. G.; Theodoridis, C.;
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Gyorvar
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