American Journal of Medical Genetics 94:249–253 (2000)
Origin of Uniparental Disomy 15 in Patients With
Prader-Willi or Angelman Syndrome
Cintia Fridman* and Célia P. Koiffmann
Department of Biology, Institute of Bioscience, University of Sâo Paulo, Sâo Paulo, Brazil
Maternal uniparental disomy (UPD) accounts for ∼25% of Prader-Willi patients
(PWS) and paternal UPD for about 2–5% of
Angelman syndrome (AS) patients. These
findings and the parental origin of deletions
are evidence of genomic imprinting in the
cause of PWS and AS. The natural occurrence of UPD individuals allows the study of
meiotic mechanisms resulting in chromosomal nondisjunction (ND). We selected patients with UPD15 from our sample of 30
PWS and 40 AS patients to study the origin
of ND and the recombination along chromosome 15. These patients were analyzed with
10 microsatellites throughout the entire
chromosome 15 (D15S541, D15S542, D15S11,
D15S113, GABRB3, CYP19, D15S117,
D15S131, D15S984, D15S115). The analysis
disclosed seven heterodisomic PWS cases
originating by meiosis I (MI) ND (four
showed recombination and three no recombination), and one isodisomic PWS UPD15
originating by postzygotic duplication.
Among the five paternal UPD15, we detected four isodisomies, three of which
showed homozigosity for all markers, corresponding to a mitotic error, and one case
originating from a paternal MII ND. Our results indicate that besides maternal MI and
MII ND, paternal ND occurs when a PWS
UPD15 patient originates from mitotic duplication of the maternal chromosome 15.
ND events in AS are mainly due to mitotic
errors, but paternal MII ND can occur and
give origin to an AS UPD15 individual by
two different mechanisms: rescue of a trisomic fetus or fertilization of a nullisomic egg
with the disomic sperm, and in this case paternal and maternal ND are necessary. Am.
J. Med. Genet. 94:249–253, 2000.
© 2000 Wiley-Liss, Inc.
Grant sponsor: FAPESP; Grant number: C.F. 95/7161-0; Grant
sponsor: PRONEX.
*Corresponding author: C. Fridman, Departamento de Biologia, Instituto de Biociências, USP, Caixa Postal 11.461. CEP:
05422-970, São Paulo, SP, Brazil. E-mail: [email protected]
Received 6 March 2000; Accepted 23 May 2000
© 2000 Wiley-Liss, Inc.
KEY WORDS: uniparental disomy; Angelman syndrome; Prader-Willi
syndrome; nondisjunction,
meiosis
INTRODUCTION
The differential expression of maternal and paternal
genetic material has been referred to as genomic imprinting [Engel, 1980; Hall, 1990]. Prader-Willi syndrome (PWS; neonatal hypotonia, hyperphagia, severe
obesity, short stature, and mental retardation with
learning disabilities) and Angelman syndrome (AS;
ataxia, seizures, sleep disorder, hyperactivity, severe
mental retardation with lack of speech, and a happy
disposition with paroxysms of laughter) are neurobehavioral disorders that result from the loss of expression of imprinted genes in the paternal and maternal
chromosome 15, respectively. This can occur through
different mechanisms such as deletion of 15q11-q13,
UPD, imprinting mutation, and mutations in UBE3A
in AS cases [Nicholls et al., 1998]. Maternal UPD accounts for ∼25% of PWS patients [Mascari et al., 1992;
Robinson et al., 1991], and paternal UPD for about
2–5% of AS patients [Bottani et al., 1994; Malcolm et
al., 1991; Nicholls et al., 1992]. These findings and the
parental origin of deletions are evidences of genomic
imprinting involvement in the PWS and AS etiology.
The origin of UPD individuals depends primarily of
nondisjunction (ND) events that can occur either in
meiosis I (MI) or meiosis II (MII). There are at least
three major mechanisms responsible for the formation
of UPD15: (1) the origin of a trisomic fetus followed by
the loss of one chromosome 15; (2) the fertilization of a
disomic egg by a nullisomic sperm (gametic complementation); and (3) postzygotic duplication [Cassidy et
al., 1992; Engel, 1993; Engel and DeLozier-Blanchet,
1991; Mascari et al., 1992; Mutirangura et al., 1993;
Purvis-Smith et al., 1992; Robinson et al., 1993a,
1993b].
The difference between the incidence of PWS UPD
and of AS UPD is attributed to the higher frequency of
ND in female gametogenesis and, as for trisomy 21, it
is correlated with increasing maternal age [Antonarakis et al., 1992; Robinson et al., 1996].
Chromosome pairing and recombination are impor-
250
Fridman and Koiffmann
tant mechanisms that assure the correct segregation of
the homologous chromosomes to the opposite poles at
the end of MI [Carpenter, 1994]. Thus, failure in homologous pairing or reduction of the recombination can
predispose chromosomes to ND [Robinson et al.,
1993a].
Robinson et al. [1998] pointed out that there are at
least two distinct mechanisms leading to ND: one related to achiasmate tetrads and one resulting in abnormal segregation of chromosome pairs with a normal
level of recombination. Despite the fact that achiasmate pairs are the preferential target for ND, it is dependent on maternal age, since in young women achiasmate pairs can segregate normally, but they are
more susceptible to ND in older women [Robinson et
al., 1998]. Recombination analysis is interesting to determine if ND occurred in an achiasmate pair or due to
an excess of chiasmata, resulting in delayed chromosome separation.
In the present study we selected patients with
UPD15 from our PWS and AS samples to study the
origin of ND and the recombination throughout the entire chromosome 15, to contribute to the understanding
of the meiotic and mitotic mechanisms responsible for
the etiology of the PWS and AS.
MATERIAL AND METHODS
The UPD cases were obtained from a sample of 30
PWS and 40 AS patients diagnosed by methylation pattern studies of SNRPN exon 1 (data not shown).
These UPD patients were investigated by analysis of
10 microsatellites throughout the entire chromosome
15 (D15S541 and D15S542 [Christian et al., 1995],
D15S11, D15S113 and GABRB3 [Mutirangura et al.,
1993], CYP19 [Polymeropoulos et al., 1991], D15S117,
D15S131, D15S984 and D15S115 [Dib et al., 1996])
(Fig. 1). The origin of nondisjunction was established
using the most centromeric markers (D15S541 and
D15S542). The heterodisomic state of these markers
indicates an MI error and their isodisomy indicates
nondisjunction in the MII stage or a postzygotic event
[Robinson et al., 1993a].
The other markers allowed us to disclose crossover
regions (transition from hetero- to isodisomy and vice
versa) in each case. The mitotic error was considered
when all markers showed reduction to homozygosity.
The genomic DNA (100 ng) was amplified in a polymerase chain reaction (PCR) of total volume of 10 ␮l,
with an initial denaturation for 4 min at 94°C. Thirty
cycles were run, with denaturation for 30 sec at 94°C,
annealing for 1 min at 55°C, and extension for 45 sec at
72°C. The final extension was for 6 min at 72°C. The
microsatellites D15S11, GABRB3, and D15S113 were
amplified by the method of Mutirangura et al. [1993] in
a multiplex PCR. The PCR products were applied to a
4.8% polyacrilamide gel and electrophoresed for 3
hours followed by exposure to an X-ray film for 24
hours.
RESULTS
Out of a total of 30 PWS patients, 8 (23.4%) were
found to have maternal UPD, 18 (53%) a paternal de-
Fig. 1. Physical and genetic map of
the markers used in UPD study. The order of the markers and the distances
(cM) are based on Dib et al. [1996] and
Robinson and Knoll [1997].
UPD in PWS and AS
letion of 15q11-q13, and 4 were uninformative regarding the genetic mechanism. Among 40 AS patients, 5
(12.5%) presented paternal UPD, 24 (60%) showed maternal deletion of 15q11-q13, 3 were uninformative,
and 8 were normal for all genetic tests but continued to
have a clinical diagnosis of AS.
By analyzing 10 microsatellite loci (CA repeats)
spanning 15q we identified the meiotic origin of ND in
all cases of UPD but two (patient 4, PWS; and patient
11, AS), and also the number of transitions (⳱observed
changes in marker state between heterodisomy and
isodisomy) in each case. Although in patient 4 (PWS) it
was not possible to establish the meiotic origin of ND,
we considered this case as a heterodisomy since the
D15S11 locus is mapped only 3cM from the centromere
(Fig. 1). In patient 11 (AS) it was not possible to disclose the origin of ND because there was no paternal
sample for analysis and only two loci were informative
within the PWS/AS region. The results were interpreted according to Robinson et al. [1993a].
Thus, we disclosed seven PWS heterodisomies originating from maternal MI ND (three showed heterodisomy throughout the entire chromosome with no evidence of recombination [patients 4, 5, and 6]) and four
with some loci showing hetero- and others isodisomy
(patients 1, 3, 7, and 8)], 1 AS isodisomy (MII paternal
251
error, patient 10), four isodisomies resulting from mitotic errors (1 PWS [patient 2] and 3 AS [patients 9, 12,
and 13]). AS patient 9 was really an isodisomy due to a
translocation 15;15 that was previously described
[Fridman et al., 1998]. The microsatellite results of
PWS and AS patients are shown in Table I and drawn
in Figure 2. AS patients 9, 10, 11, and 12 were already
described (Fridman et al., 2000b) corresponding to patients 1, 2, 3, and 4, respectively.
Maternal age was increased in our UPD sample.
DISCUSSION
In our UPD sample we detected eight maternal UPD
corresponding to 23.4% of the PWS group and five paternal UPD, corresponding to 12.5% of the AS group.
The maternal UPD frequency is in accordance with literature data [Nicholls et al., 1989; Robinson et al.,
1991], but we found an increase of paternal UPD in our
sample compared with others (2–3%) [Clayton-Smith
and Pembrey, 1992; Malcolm et al., 1991]. This result
could be explained by the fact that we did not use only
the diagnostic criteria suggested by Williams et al.
[1995] to consider a patient as a probable AS. We tested
patients with absence crises, seizures of late onset, and
obesity associated with outer frontal circumference
TABLE I. Results of Microsatellite Analysis of UPD15 Patients and Their Parental Ages*
M
1 PWS
F
M
2 PWS
F
M
3 PWS
F
M
4 PWS
F
M
5 PWS
F
M
6 PWS
F
M
7 PWS
F
M
8 PWS
F
M
9 AS*
F
M
10 AS*
F
M
11 AS*
F
M
12 AS*
F
M
13 AS
F
D15S541
D15S542
D15S11
D15S113
GABRB3
CYP19
D15S117
D15S131
D15S984
D15S115
1,2
1,2 NR
1,2
1,3
1,1 R
2,3
1,2
1,2 NR
1,1
2,2
2,2
1,1
1,2
1,2 NR
1,1
1,1
1,1
2,2
1,2
1,2 NR
1,1
1,1
1,1
1,2
3,4
1,1 R
1,2
2,3
1,1
1,1
1,1
2,2
–
1,3
2,2 R
2,4
2,3
1,1
1,1
2,2
2,2
1,2
1,1
1,1
2,2
3,4
3,4 NR
1,2
3,3
3,3
1,2
1,3
1,3 NR
2,2
1,2
1,2 NR
3,3
1,2
1,2 NR
1,2
1,2
1,2 NR
1,1
3,4
1,1 R
1,2
2,3
4,4 R
1,4
1,1
2,2
–
1,3
2,2 R
2,3
1,2
3,3 R
3,4
1,2
1,2 NR
1,2
1,2
2,2 R
1,3
1,1
1,1
1,2
1,2
1,2 NR
2,2
1,2
1,2 NR
1,2
2,3
2,3 NR
1,4
1,1
1,1
2,2
1,3
1,3 NR
2,4
2,4
1,1 R
1,3
1,2
1,1 R
1,3
–
–
–
–
–
–
3,3
1,1 R
1,2
2,3
2,3 NR
1,1
2,2
2,2
1,1
1,3
1,3 NR
2,2
1,2
1,2 NR
1,3
1,2
1,2 NR
1,2
3,3
3,3
1,2
1,2
1,2 NR
2,2
1,3
1,3 NR
1,2
1,1
1,1 R
1,2
2,3
2,2 R
1,2
1,4
2,3 NR
–
2,2
1,1 R
1,3
1,1
1,1
1,1
3,3
3,3
1,2
2,3
2,2 R
1,2
1,2
1,2 NR
3,4
1,2
1,2 NR
2,3
2,3
2,3 NR
1,1
1,1
1,1
1,2
1,2
1,2 NR
1,1
1,2
1,2 NR
3,3
1,2
3,3 R
3,3
3,3
1,1 R
1,2
2,3
1,2 NR
–
1,1
2,2 R
2,3
3,4
2,2 R
1,2
2,4
2,4 NR
1,3
2,2
2,2
1,1
1,2
2,2 R
1,2
1,2
1,2 NR
1,1
–
–
–
1,3
1,3 NR
1,1
2,3
2,3 NR
1,3
1,2
2,2 R
1,2
1,4
2,2 R
2,3
1,1
1,2 NR
1,2
1,3
2,2
–
2,4
1,1 R
1,3
1,1
1,1
1,2
1,4
1,1 R
2,3
1,2
1,1 R
1,2
1,4
4,4 R
2,3
1,3
1,3 NR
2,3
1,1
1,1
2,3
2,3
2,3 NR
1,4
2,3
3,3 R
1,4
2,3
3,3 R
1,4
2,2
3,3 R
1,3
2,3
1,4 NR
1,4
1,2
1,1
–
1,2
4,4 R
3,4
1,2
3,3 R
3,4
1,2
2,2 R
1,3
1,4
1,1 R
2,3
2,3
2,2 R
1,1
2,2
2,2
1,4
–
2,3 NR
1,2
2,3
2,3 NR
1,4
3,4
3,4 NR
1,2
1,3
1,3 NR
2,3
3,3
3,3 R
1,3
1,3
2,4 NR
2,4
1,2
1,1
–
1,2
2,2 R
2,3
–
–
–
1,3
1,1 R
2,2
2,2
2,2
1,3
1,2
1,1 R
3,4
2,3
2,3 NR
1,4
1,4
1,4 NR
2,3
1,3
1,3 NR
2,4
2,3
3,3 R
1,2
2,4
2,4 NR
1,3
2,3
2,2 R
1,2
2,3
1,1
1,1
1,3
2,2
–
1,3
3,3 R
2,3
1,2
4,4 R
3,4
1,2
1,2 NR
3,4
2,3
3,3 R
1,1
3,3
3,3
1,2
1,3
1,3 NR
1,2
1,2
1,2 NR
1,3
2,3
2,3 NR
1,4
1,2
1,2 NR
1,2
1,3
1,3 NR
2,3
1,2
4,4 R
3,4
2,2
1,3 NR
1,3
1,2
2,2
–
1,3
4,4 R
2,4
3,4
1,1 R
1,2
*Results already presented in Fridman et al. [2000b]. R, reduction; NR, non reduction; M, mother; F, father; –, not tested.
Maternal
age (years)
Paternal
age (years)
41
50
32
34
37
40
19
21
37
37
36
32
46
50
42
44
30
33
40
47
23
25
29
37
37
39
252
Fridman and Koiffmann
Fig. 2. Schematic results of UPD PWS
(A) and AS (B) patients and the localization
of the markers along chromosome 15. HET,
heterodisomy; ISO, isodisomy; NI, noninformative; NT, not tested; NR, nonreduction; R,
reduction.
(OFC) above the 75th centile. In this way, we included
cases that probably are borderline for the still incompletely known phenotypic spectrum of AS [Fridman et
al., 1998; Fridman et al., 2000b].
As reported previously [Mascari et al., 1992; Mutirangura et al., 1993; Robinson et al., 1993a, 1996] we
also detected a higher incidence of maternal ND at MI
in PWS UPD15 patients and mitotic errors in AS
UPD15 cases. These results confirm that most maternal ND events resulting in UPD15 PWS are associated
with MI errors, with rare cases being MII or due to
postzygotic errors, whereas most paternal UPD15
seems to be postzygotic events.
Recombination was detected in four maternal and
one paternal UPD15 (patient 10; Fridman et al., 2000a)
(Fig. 2). Robinson et al. [1993a] suggested that the use
of markers with intervals of 20 cM is sufficient to observe most crossover events. Although some markers
used here were mapped less than 20 cM from each
other, we could observe recombination, as shown in pa-
tients 1 and 7, where there is a transition from heterodisomy (nonreduction) to isodisomy (reduction) between the loci CYP19 and D15S117, localized 8 cM
from each other, and transition from reduction to
nonreduction between the loci D15S984 and D15S115,
mapped 7 cM from each other (Table I; Fig. 2).
In three maternal UPD15 cases we cannot conclude
that there was no meiotic recombination since both homologous chromatids that segregated together could be
the two involved in the crossover, and then the recombination event would not be observed. These cases can
also represent achiasmatic pairs, and so there are no
crossover points.
In our UPD PWS sample we also observed an increase in maternal age (Table I) confirming that, also
for chromosome 15, there is a correlation between increased maternal age and nondisjunction.
It is interesting to note that in postzygotic errors
resulting in PWS individuals with UPD15 (such as patient 2) the primary event is a paternal rather than a
UPD in PWS and AS
maternal ND, since the fertilization of a normal egg
with a nullisomic sperm followed by a mitotic duplication of maternal chromosome 15 is necessary. In AS the
postzygotic errors are associated with increased maternal age since the primary event is the maternal ND
followed by the fertilization of the nullisomic egg with
a normal sperm and later duplication of the paternal
chromosome in the zygote.
The origin of an AS patient with isodisomy due to
MII error [Fridman et al., 2000a] can be attributed to
two mechanisms: paternal ND in MII and fertilization
of a normal egg with this disomic sperm originating a
trisomic fetus with the later loss of the maternal chromosome; or the fertilization of a disomic sperm with a
nullisomic egg, for which a maternal and a paternal
ND is necessary.
In conclusion, in the sample of eight PWS UPD15
cases we detected seven with heterodisomy originated
by MI ND, of which four showed recombination and
three no recombination along chromosome 15. One
PWS UPD15 was an isodisomy that was probably originated by an event of mitotic duplication, rare in PWS.
In the sample of five paternal UPD15, we detected four
isodisomies, three of which showed homozygosity for
all markers, corresponding to a mitotic error or, alternatively, to a MII meiotic error where no recombination
has occurred in MI, and one case was originated by a
paternal MII ND since it showed a recombination
point. The fifth case was uninformative regarding the
meiotic origin of ND.
The natural occurrence of UPD individuals allows
the study of the meiotic mechanisms resulting in chromosomal ND and the understanding of the influence of
parental age on this process. Although the frequency of
UPD15 is not comparable with that of trisomy 21, it
would be of utmost interest to determine the parental
origin of both chromosomes 15 in women undergoing
prenatal diagnosis for advanced maternal age.
253
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