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Deep Insight Section
Some lessons from uniparental disomy (UDP) in
the framework of comtemporary cytogenetics and
molecular biology
Eric Engel
Department of Medical Genetics and Development, University of Geneva, Geneva, Switzerland (EE)
Published in Atlas Database: December 2003
Online updated version: http://AtlasGeneticsOncology.org/Deep/UniparentDisomyID20046.html
DOI: 10.4267/2042/38086
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
This is an ambitious title to deal with.
Of course, UPD refers to the accidental presence of a
chromosome pair or a chomosome segment derived
from only one parent in a diploid individual.
In fact, the information on this subject has grown so
large that Pub Med, the webb-site of the US National
Library of Medecine, by now lists over 550 original
titles not to mention the so-call related articles.
In the bulk of this material. I particulary like to stress
the elegant contributions from Prs Lidia Larizza,
Orsette Zuffardi and their colleagues on the role of
parental chromosome 15 inversions in subsequent
segmental deletions of that chromosome and their study
of UBE3A mutations in AS.
I also want to mention the wealth of information and
observations that we owe to Pr A Schinzel and his
group and to Dr Dietrich Kotzot in this area.
Lidia, Albert, I thank you whole-heartedly, as well as
the Organizing Committee and Dr Konstantin Miller
for inviting me to address the Audience of this select
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
ECA Meeting in Bologna. Thank you, indeed for your
hospitality.
146
Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Engel E
Slide 1
I thus started in the field at this most exciting period
wich I call the Golden Years. Within two of these
years, 1959 and 1960, the three major autosomal
trisomies, G, E, and D, namely 21, 18 and 13 turned up
along with three of the four more common sex
chromosome anomalies. XXY, XXX, XO (the XYY
would appear later), plus the first example of human
chromosome mosaicism.
We all known the prestigious names of the Scientists
listed here, wich include two illustrious pionneers of
this Country, Marco Fraccaro and Paul Polani.
These achievements had been acquired at the cost of
great efforts, particulary with respect to the cultures of
the solid tissues or marrow samples, needed to offer the
sight of our chromosomes.
Slide 2
EASIER CELL CULTURE PREPARATIONS :
Moorehead PS, Nowell PC, Mellman WJ,
Batipps DM and Hungerford :
Chromosome preparations of leukocytes cultured
from human peripheral blood
Exp Cell Research 1960, 20, 613
In this context, the opportunity of using a few drops of
venous blood for short term culture and chromosome
studies
with
Phytohemagglutinin
for
blast
tranformation of monolymphocytes represented a boon
to all interested personnel.
1960 is precisely the time when I joined the MGH in
Boston and began setting up there a Cytogenetic
laboratory.
Slide 3
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
147
Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Other notable discoveries occurred in the sixties in our
field, including the sighting of some tiny deletions, but,
just as happened in the early years of photography, the
chromosomes appeared uniformely dark over a clear
white background.
This is not to say that we could not see very interesting
details such as they dislpayed here, with the Ph1
chromosome, a dicentric 17-18 E chromosome and a
D/D translocation - the later congenital - in this
example of the clonal pattern of a leukemic cell at the
blast phase of CML.
Slide 4
Slide 5
AVORTEMENTS ANEUPLOïDES DU PREMIER TRIMESTRE
50 % DU TOTAL :
1/2 TRISOMIE
AUTOSOMALE
1/5 MONOSOMIE X
1/3 POLYPLOïDIE
HASSOLD T.J. & AL ANN. HUM. GENET. (Lond.) 41, 443454, 1978.
We had come to learn that one half or so of these
aborted fetuses showed major chromosome anomalies,
half of them as a trisomy, one fifth as an X-monosomy
and one third as a polyploidy, mostly triploidies.
SPECIFIC CHROMOSOME
(ANALYTICAL
BANDING) IDENTIFICATION
Casperson T, Zech L, Johansson C, Modest EJ.
Identification of human chromosomes by DNA-binding
fluorescent agents.
Chromosoma. 1970 30:215-27.
Slide 6
PRINCIPALES TRISOMIES DES AVORTEMENTS
ANEUPLOïDES DU PREMIER TRIMESTRE
Couturier J, Dutrillaux B, Lejeune J.
Specific fluorescence of R and G bands in human
chromosomes.
CR Acad Sci 1973 276:339-342
As I just said earlier, the specfic identification, as of
1969-1970
of
individual
chromosomes
by
fluorochromes pionnered thanks to Caperson, Zech et
al. and also obtained by other banding procedures
devised by Seabright, Dutrillaux and other major
contributors changed the whole ball game.
And, it is under the benefit of so much technical
sophistication that I shall now quickly review the
cytogenetic results gained from the systematic studies
of the product of first trimester spontaneous abortions.
They all pointed to the high rate of gamete aneuploidy,
as a fact of observation which served as the basic of the
UPD concept and suggested the fairly simple idea that,
sometimes, somehow a diploid individual might be
conceived or could develop, with one of the 23
chromosome pairs from one single parent.
47, +16
32 %
47, +21
13 %
47, +15
10 %
47, +22
13 %
CREASY M.R. & AL. : HUM. GENET. 31. 177-196. 1976.
And, among the trisomies, four of them largely
prevailed, namely trisomy 16 in one third of the cases,
and trisomies 21, 22 and 15, each accounting for about
10 % of the lot, thus making up altogether some two
thirds of the trisomies observed in these abortuses.
And since, as a rule, meiotic mis-segregation must
result in as many nullisomie as disomic gametes, it did
not seem to me too far-fetched an idea to statistically
envisage the following possibility, namely that
coincidental fertilization and complementation of a
nullisomic gamete by one disomic for a same
chromosome might indeed occur, thus occasionally
causing a diploid conceptus to derive one pair from
only one parent.
Thus, on the basis of the figures documented for the
rate of aneuploidy limited to these four autosomes
Slide 7
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
Engel E
148
Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Engel E
through
appropriate
enzyme
restriction,
electrophoresis and adequate marking.
Slide 10
and the X and making some asumptions wich I shall
not her develop, it looked as follows : for a toll of 20 %
abortions of all conceptuses, one half of which were
aneuploid, complementation at fertilization for these 5
member chromosomes causing UPD for one of these
pairs might occur with the incidences reported here. In
brief, on those premisses, one might envisage 2 or 3
cases of putative UPD for one or the other of these 5
members every 10,000 births and even more when
considering an abortion frequency of 50 % !
Slide 8
gel
PUTATIVE CONSEQUENCES OF
UNIPARENTAL DISOMY
(as considered in 1979)
The birth of Mendelian non traditional
inheritance
1) Homozygous traits inheritable from one
carrier parent only
In this diagram from our book, individual 3 has an
allele from each parent, as normal and individuals 4
and 5 have only paternal alleles, two contrasted ones
for individual 4i.e. heterodisomy and two identical ones
for offspring No. 5, the so-called isodisomy. Also it is
of note that if this duplicated allele was that of a
recessive trait, the individual would be affected.
Slide 11
2) Father to son exceptional transmission of an
X-linked trait
3) Xg(a-) daughters born to Xg(a+) legitimate
fathers
4) Affected daughters born to recessiv X-linked
carrier mothers
5) Duplication of chromosomal markers morphological or molecular - present in only
one parent
Am. J. hum. Genet. 42: 215-216, 1988
Editorial : Uniparental Disomy: A Rare Consequence of
the High Rate of Aneuploidy in Human Gametes
Dorothy Warburton
If that were to happen what might be the occasionnal
consequences of deriving one chromosome from one
parent only?
Slide 9
Department of Genetics and development of Pediatrics,
Columbia University. New York
Am. J. hum. Genet. 42: 217-225, 1988
Uniparental Disomy as Mechanism for Human Genetic
Disease
American Journal of Medical Genetics 6: 137-143 (1980)
A New Genetic Concept: Uniparental
Disomy and Its Potential Effect, Isodisomy
J. Edward Spence, Ronald G. Perciccante, Guillian M.
Greig. Huntington F. Willard. David H. Ledbetter. J.
Fielding Hejtmancik, Marilyn S. Pollack, William E. O'Brien
and Arthur L. Baudet
Howard Hughes Medical Institute, Institute of Molecular
Genetics and Department of Microbiology and
Immunology, Baylor College of Medicine, Houston: Mercy
Hospital, Watertown, NY: and Department of Medical
Genetics, University of Toronto, Toronto
Eric Engel
Institute of Medical Genetics, Geneva University School
of Medicine, Geneva, Switzerland
In recent years, cytogenetic studies of spontaneous
abortion products have disclosed a relatively high
frequency of aneuploid embryos. These karyotypic
anomalies chiefly stem from meiotic errors affecting the
distribution of the chromosomes in one of two gametes.
This information not only implies the remarkable
frequency of gonocyte aneuploidy but also reveals the
pre
And this is precisely the mechanism which helped these
investigators to uncover the first thoroughly analyzed
and described case of UPD. It was one involving
maternal chromosome 7, responsible for cystic fibrosis
in an unusually short girl who carried Gly542Ter
mutation in her CFTR gene.
This article, of Beaudet’s lab, with Ledbetter among the
Authors and Spence as the Senior Author, was not only
featuring the first case ever sighted of non-traditional
recessive
inheritance
through
reduction
to
homozygosity of the recessive mutant only carried by
one of the two parents. It also offered a most
comprehensive review of the possible mechanisms
leading to the occurrence of UDP.
And thus, after many months of cogitation, I came to
spend one night, from a saturday to a sunday, to put
down a draft of this idea in writing.
Once in print and published, the idea slept in the
medical literature for some years because, at the time of
the publication, 1980, the means to trace the parental
origin of a chromosome were still limited, awaiting the
analyses of DNA polymorphisms as schematically
shown here. Given the four constrated alleles of a
particular locus in two parents, each one can be traced
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
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Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Interestingly enough the journal Science rejected this
report, apparently for describing a situation too
exceptional for a broad readership; and, while accepted
for publication by the American Journal of Human
Genetic, the accompanying editorial almost echoed the
very reasons why the other major publications had
Engel E
turned down the article. It is precisely at this junction
that I would like to review the list of some thirty or so
different recessive conditions traced to this very
mechanism over the last 14 years. Some of these have
indeed been observed more than once.
Slides 12
UNIPARENTAL ISODISOMY
REDUCTION TO HOMOZYGOSITY LEADING TO RECESSIVE DISORDERS (1)
Recessive Disorders
UDP type
References
Pycnodysostosis
1 pat
Gelb et al. (1998)
Junctional epidermolysis bullosa, Herlitz type
1 mat
Pulkkinen et al. (1997)
Spinal muscular atrophy III (juvenil type)
5 pat
Brzustowicz et al; (1994)
Complement deficiency of C4A+C4B
6 pat
Welch et al. (1990)
Methylmalonic acidemia
6 pat
Abramowicz et al. (1994)
Cystic fibrosis
7 mat
Spence et al. (1988), Voss et al. (1989)
Osteogenesis imperfecta (COL1A2 mutation)
7 mat
Spotila et al. (1992)
Cystic fibrosis and Kartagener syndrome
7 pat
Pan et al. (1998)
Congenital chloride diarrhea
7 pat
Hôglund et al. (1994)
Chylomicronemia, familial
8 pat
Benlian et al. (1996)
Cartilage / hair hypoplasia
9 mat
Sulisalo et al. (1997)
Beta-thalassemia major
11 pat
Beldjord et al. (1992)
Complete congenital achromatopsia (rod monochr.)
14 mat
Pentao et al. (1992)
Bloom syndrome (with Prader-Willi syndrome)
15 mat
Woodage et al. (1994)
Hydrops fetalis alpha-thalassemia
16 pat
N'go et al. (1993)
Duchenne muscular dystrophy
X mat
Quan et al. (1994)
XY
Vidaud et al. (1989)
Hemophilia A
EE (2/10/1998)
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
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Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Engel E
UNIPARENTAL ISODISOMY
REDUCTION TO HOMOZYGOSITY LEADING TO RECESSIVE CONDITION (part 2)
1999-2003
CONDITION
UDP type
Chediak-Higashi Syndrome
1 mat
Dufourcq-Lagelouse et al
1999
Mapple Syrup Disease Type II
1 mat
Lebo et al
2000
Congenital insensivity to pain, anhydrosis
(CIPA)
1 pat
Miura et al
2000
Herlitz junctional epidermolysis bullosa
1 pat
Takizawa et al
2000
Mosaicism Rh+/Rh-
1 pat
Miyoshi et al
2001
CIPA+Pyruvate kinase receptor deficiency
1 pat
Indo et al
2001
Leber congenital amaurosis
1 pat
Thomson et al
2002
Retinis, Usher type II
1 pat
Rivolta et al
2002
Lactic acidosis (trifunctionnal protein
deficiency)
2 mat
Spiekerkoetter et al
2002
Idem
AUTHORSHIP
idem
idem
Pseudohermaphroditism (5-alpha reductase
deficiency)
2 pat
Chavez et al
2000
Retinis pigmentosa (MERKT)
2 pat
Thompson et al
2002
A-betalipoproteinemia
4 mat
Yang et al
1999
21-Hydroxylase deficiency
6 pat
Lopez-Guttierez et al
1998
Cystic fibrosis
7 mat
Hehr et al
2000
Leigh syndrome
9 mat
Tiranti et al
1999
EE july 2003
Slide 13
In some studies, particularly the first ones listed here,
one can get some idea of the condition of reduction to
homozygosity to recessive traits as compared to that of
classical biparental recessive inheritance which ranges
from up to 2 to 4 % in the series with more than 50
cases tested.
And, it is as much as I shall now devote to this aspect
of non-traditional inheritance in UPD.
Slide 14
Nicholls RD, Knoll JH, Butler MG, Karam S,
Lalande M.
Howard Hughes Medical Institute; Havard
Madical School, Boston, Massachusetts.
I now turn to another major player in the field of UPD,
brought into action by Rob Nicholls et al, the
phenomenon of genomic imprinting.
But, to bring that up, let me first refer to the well know
and significant observation of a tiny 15q11q13 deletion
in the Prader-Willi syndrome, by David Ledbetter and
colleagues in 1981.
Nature 1989. 342: 281-5
Genetic imprinting suggested by maternal
heterodisomy in nondeletion Prader-Willi
syndrome.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
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Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Engel E
Slide 15
It did take wonderful eyes to detect such a small, albeit
most important cytogenetics detail!
Slide 16
It was Rob Nicholls and colleagues’ merit to establish
that in the rarer cases of PWS without the tiny deletion,
a chromosome pair 15 looked pink, painted exclusively
of maternally segregating alleles and markers (!!).
Thus, in these instances, these rarer cases showed
maternal UPD 15, along with the lack of a paternal
chromosome 15.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
The obvious lesson to it was that an intact second
maternal 15 could not substitute successfully for the
missing paternal one. Therefore, in this instance,
although normal looking, the second maternal
chromosome 15 was lacking the genetic expression of a
proper paternal one. Why was it so? Indeed this very
observation was to serve at the introduction of a still
poorly understood phenomenon, genomic imprinting.
152
Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Slide 17
Engel E
2) EVANS HK et al 2001
Both paternal and maternal chromosome 20 show an
imprinting mark, which, on the maternal side, allows
sensitivity to parathormone and, on the paternal side,
expresses a protein essential for embryofetal neurologic
development.
Definition : Genomic Imprinting
the epigenetic modification of certain genes through
methylation as a function of their parental origin
>> an "imprinted" gene is often considered to
be an inactived gene
>> the result is functional hemizygosity
(maternal or paternal) for some allelic pairs
>> imprint "relaxation" normally occurs early in
gametogenesis
Slide 20
We can see on it a fairly simple reminder of the
definition of genomic imprinting.
Slide 18
This slide shows what proportion of some well defined
syndromes might be caused by a given uniparental pair
proven responsible for disrupting the normal imprinting
process.
Slide 21
With time and patience, it was recognized that the
imprinting disruption caused by the possession of a
UPD pair could intervene as a cause of some
previously known syndrome as well as a help in
delineating some new ones.
UPDs, maternal or paternal, for chromosomes 6, 7, 11
and 15 have occured in a variable proportion of the
listed syndromes, while both maternal and paternal
UPD 14 each delineated a new syndrome.
Three other pairs came under suspicion of exercising
harmful effects through a similar mechanism, although
such an interference appears less and less certain for
maternal chromosome 2, still quite likely for maternal
chromosome 16 and definite for chromosome 20, both
paternal and maternal, a topic in full evolution.
The figures on slide 21 lend support to some
extrapolation to evaluate the baseline frequency of a
few of the viable UPDs involved as a cause disease.
Thus, if the PWS phenotype is in general viable and
knows a clinical frequency of 1 in 20,000 live births,
and if maternal UPD 15 serves as an etiology for some
25 % of these cases, one may infer that maternal UPD
15 occurs around once every 80,000 live births. And so
on for several other UPDs causing a proportion of
syndromic conditions of reasonably well documented
overall frequencies.
Slide 19
CHROMOSOME 20 "MICRO - IMPRINTING"
GNAS1 (GUANINE NUCLEOTIDE BINDING PROTEIN) 1
MAPS AT 20q13.3
MATERNALLY EXPRESSED (PATERNALLY INACTIVE)
ENCODES ALPHA-SUBUNIT OF STIMULATORY G PROTEIN (Gsb)
NEEDED FOR RECEPTOR STIMULATED cAMP GENERATION
LOSS CAUSES RESISTANCE TO PTH
NNA1 (NEURONATIN) 2
MAPS AT 20q11.2
PATERNALLY EXPRESSED (MATERNALLY INACTIVE)
ENCODED DEDUCED PROTEIN IS A PROTEOLIPID
IMPORTANT ROLE IN EMBRYO-FETAL NERVOUS SYSTEM
DEVELOPEMENT
1) LIU et al 2000
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
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Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Engel E
Slide 22
So far we have in this lecture followed two leads, one
looking at the UPDs recognized as the cause of
recessive traits, the other as a cause of malformations
through the normal process of genomic imprinting.
At this junction, in guise of more systematic
approach, we can review, as shown here, the 47
possibilities of UPD for wholesale chromosomes,
namely 22 paternal and 22 maternal pairs for the
autosomes as well as 3 more pairs for the sex
chromosomes, one maternal XX and two paternal ones,
namely XX or XY.
Slide 23
TYPES OF MATERNAL OR PATERNAL UPD's KNOWN OR
UNDECTECTED
A)
B)
C)
18 KNOWN MATERNAL TYPES
1
2
4
6
7
8
9
10
12
13
14
15
16
17
20
21
22
14 KNOWN PATERNAL TYPES
1
2
5
6
7
8
11
13
14
15
16
21
22
5
11
18
19
10 UNKNOWN PATERNAL TYPES
3
4
9
10
12
17
18
19
20
X
On this next slide, we show somewhat arbitrarily the
chromosome numbers, maternal or paternal, which
have contributed a monoparental pair in the make up of
one purely and uniformly diploid genome, assuming
that the available information allowed an exclusion of
the mosaic compounded by an aneuploid component.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
XY
5 KNOWN MATERNAL TYPES
3
D)
X
This review is comprised of 18 maternal and 14
paternal numbers, for a total of 32. Thus some 15
numbers are still currently without inclusion in a
uniparental pair, if we disregard paternal 20 and
paternal X, so far only noted in an aneuploid mosaic
context.
154
Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Engel E
Slides 24
TIMING OF THE FIRST IDENTIFICATION OF EACH OF 32 TYPES OF UPD's
YEAR
1987
TYPE
21 mat
AUTHORSHIP
Créau-Goldberg et al
1988
7 mat
1989
15 mat
Nicholis et al
1989
XY
Vidaud et al
1990
6 pat
1991
11 pat
Spence et al, Voss et al
Weich et al
Grundy et al
1991
4 mat
1991
14 mat
Lindenbaum et al
Temple et al
1991
14 pat
Wang et al
1991
15 pat
Malcolm et al
1992
16 mat
Benett et al
1993
21 pat
Blouin et al
1993
16 pat
N'Go et al
1994
22 mat
Schinzel et al
1994
5 pat
Brzustowicz et al
1994
7 pat
Höglund et al
1995
2 mat
Harrison et al
1995
10 mat
Jones et al
1995
13 mat
Stallard et al
1995
13 pat
Slater et al
1995
22 pat
Miny et al
1996
8 pat
Benlian et al
1996
6 mat
Van den Berg Loonen
1997
1 mat
Pulkkinen et al
1997
8 mat
Piantadina et al
1997
9 mat
Sulisalo et al
1997
X mat
Quan et al
1998
1 pat
Gelb et al
1998
20 mat
Chuboda et al
1999
17 mat
Genuardi et al
2002
2 pat
Thomson et al
2002
12 mat
Von Eggling et al
EE july 2003
Both these slides show the pace at which these
uniparental pairs were uncovered since the first ones
were identified.
We only see a few in the first decade following
publication of the concept. Many more are documented
in the 5 years from 91 to 95 and still quite a few are
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
observed in the last 7 years till now, to the best of my
knowledge.
It will be interesting to see which others will be
detected in the forthcoming years to finally assume that
those never seen are, may-be, lethal.
155
Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Engel E
Slide 25
I would like to devote the rest of my talk to some
peculiar machanisms of UPD formation. I have selected
these examples because, to me, they illustrate some
incredible twists of Nature.
I first aim at showing the role of some so-called non
homologous
or
homologous
Robertsonian
translocations or centric fusions of acrocentric
chromosomes.
You see here, at first glance, a non-homologous
balanced translocation which, through an adjacent
meiotic separation, produces a disomic gamete. This
segregant, upon fertilization, generate a trisomic
conceptus. If UPD must result, of two possible new
hits, one will take off the singly inherited number,
leaving behind a UPD pair made of one free and one
attached acrocentric chromosome.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
According to Lisa Shaffer and colleagues, this will
happen in 0,6 % or so of prenatally diagnosed
Robersonian translocations but the toll will rise to
about 4 % when prospecting a cohort of phenotypically
abnormal carriers.
On the other hand, two thirds of the bearers of
homologous centric fusions will display a uniparental
pair for the involved number.
On this slide below, precisely, a pattern of homologous
centric fusion for chromosome 22 is found in a woman
who aborts ten times in a row before producing a
normal female offspring who, in turn, in due time will
abort seven times.
156
Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Slide 26
Slide 27
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
157
Engel E
Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Dealing in more details into this siuation, we see that
eggs with the segregation of this homologous centric
fusion can, upon fertilization, only produce monosomic
or trisomic 22 inviable abortion products !
The only healthy offspring must have resulted from
gamete complementation or, more likely, from the very
early embryonic loss of parental 22. Such a luck in this
case will not occur at the next generation in spite of 7
trials ending in as many abortions.
In the next example, an homologous 13/13 centric
Engel E
fusion or an isochromosome 13q (or an isodicentric 13)
is found in a balanced woman withot a maternal 13.
She thus examplifies a case of paternal UPD 13.
She, in turn, produces a balanced male offspring born
after 5 spontaneous abortions. This balanced offspring
carries the same 13/13 fusion as his mother, thus
harboring a maternal UPD 13 without a traceable
paternal13.
Here, amazingly, UPD 13 has taken place over two
generations, once of paternal and once maternal origin,
while the other parental 13 has not made its way in the
embryonic cells ! A true miracle !
Slide 28
Slide 29
On this slide, we see how a parental 13/14 evidently
non homologous Robertsonian translocation in a father
ends up into an isochromosome 14 in a son with the
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
syndrome of maternal UPD 14! An adjacent
segregation has resulted into a nullisomy 14 in a
paternal gamete whose deletion has been apparently
158
Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Engel E
Sometime the UPD does not involve the whole of a
chromosome and remains confined to a segment of a
pair as it arises from a somatic crossing over between
two homologous non-sister chromatids. When
interstitial, the segmental UPD results from two
symmetrical breaks, which are shown here as the result
of an �interchromatid kiss� ! Mitotic segregation
of the duplicated chromosomes, thereafter leads to
mosaicism with one native and one reshuffled balanced
cell line.
patched up by duplication of the maternal 14 into an
isochromosome, after fertilization.
Slide 30
Slide 32
And, since isochromosomes for acrocentrics have now
just been mentioned, let me show, again from literature,
some examples of UPD resulting from the presence of
two isochromosomes per balanced individual genomes,
namely one for each arm of a biarmed chromosome
such a number 1, 2 (twice), 4, 7 or 9. Besides, in the
case of Eggerding et al, the short arm isochromosome 7
was paternal ad the isochromosome for the long arm
was maternal in origin. Most remarkable, is not it?
In other instances the segmental UPD is terminal and
results from a single symmetrical break in each of two
homologous non-sister chromatids, as seen here.
Mosaicism involving two somatic cell types also results
from this.
On this slide below are presented examples of both
types of segmental UPD, terminal or interstitial, as
found for various chromosomes, 4, 6, 7, 11, 14, 20.
Some were discovered because of reduction to
homozygosity causing recesive traits, while others
involved imprinted domains and disrupted them.
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Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Slide 33
Slide 34
Here are briefly reviewed some modes of UPD
formation for more commonly affected member
chromosomes.
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Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Slide 35
This summary slide attempts to compile the information developed in this presentation.
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Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.
Engel E
Slide 36
Slide 37
This slide shows a source to find more information
from a book written witn my friend and Colleague
Stylianos Emmanuel Antonarakis which was published
in 2002 by Liss-Wiley in New York.
My last slide is a symbol of my indebtedness to the
many Authors who gave so much life to so simple an
idea.
In this composite picture the dwarf sitting on the
shoulders of the giant is the personn who sees the
farthest.
My thanks go to Mr. Jean-Claude Malgouyres for
assistance in preparing the graphic material for this
lecture.
This article should be referenced as such:
Engel E. Some lessons from uniparental disomy (UDP) in the
framework of comtemporary cytogenetics and molecular
biology.. Atlas Genet Cytogenet Oncol Haematol. 2004;
8(2):146-162.
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162