Microdeletion of LIT1 in Familial Beckwith-Wiedemann Syndrome

Department of Biomedical Sciences, Tottori University, TTJ, Tottori, Japan
The American Journal of Human Genetics (Impact Factor: 10.93). 12/2004; 75(5):844-9. DOI: 10.1086/425343
Source: PubMed
Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth, midline abdominal wall defects, macroglossia, and embryonal tumors, is a model for understanding the relationship between genomic imprinting, human development, and cancer. The causes are heterogeneous, involving multiple genes on 11p15 and including infrequent mutation of p57(KIP2) or loss of imprinting of either of two imprinted gene domains on 11p15: LIT1, which is near p57(KIP2), or H19/IGF2. Unlike Prader-Willi and Angelman syndromes, no chromosomal deletions have yet been identified. Here we report a microdeletion including the entire LIT1 gene, providing genetic confirmation of the importance of this gene region in BWS. When inherited maternally, the deletion causes BWS with silencing of p57(KIP2), indicating deletion of an element important for the regulation of p57(KIP2) expression. When inherited paternally, there is no phenotype, suggesting that the LIT1 RNA itself is not necessary for normal development in humans.


Available from: Kazuhiro Murakami
Am. J. Hum. Genet. 75:844–849, 2004
Microdeletion of LIT1 in Familial Beckwith-Wiedemann Syndrome
Emily L. Niemitz,
Michael R. DeBaun,
Jonathan Fallon,
Kazuhiro Murakami,
Hiroyuki Kugoh,
Mitsuo Oshimura,
and Andrew P. Feinberg
Predoctoral Program in Human Genetics and
Departments of Medicine, Molecular Biology and Genetics, and Oncology, Johns Hopkins
University School of Medicine, Baltimore;
Division of Pediatric Hematology-Oncology, Department of Pediatrics, Washington University
School of Medicine, St. Louis; and
Department of Biomedical Science, Graduate School of Medical Science, Tottori University, Tottori, Japan
Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth, midline abdominal wall defects, ma-
croglossia, and embryonal tumors, is a model for understanding the relationship between genomic imprinting,
human development, and cancer. The causes are heterogeneous, involving multiple genes on 11p15 and including
infrequent mutation of p57
or loss of imprinting of either of two imprinted gene domains on 11p15: LIT1,
which is near p57
,orH19/IGF2. Unlike Prader-Willi and Angelman syndromes, no chromosomal deletions have
yet been identified. Here we report a microdeletion including the entire LIT1 gene, providing genetic confirmation
of the importance of this gene region in BWS. When inherited maternally, the deletion causes BWS with silencing
of p57
, indicating deletion of an element important for the regulation of p57
expression. When inherited
paternally, there is no phenotype, suggesting that the LIT1 RNA itself is not necessary for normal development in
Beckwith-Wiedemann syndrome (BWS [MIM 130650])
rarely involves mutation of the imprinted cyclin-depen-
dent kinase inhibitor gene p57
(MIM 600856), which
is normally expressed from the maternal allele (Matsu-
oka et al. 1996; Lee et al. 1997; O’Keefe et al. 1997).
However, 40% of patients with BWS show loss of im-
printing (LOI) of LIT1 (MIM 604115), an antisense
RNA within the K
LQT1 gene (MIM 192500) and 220
kb telomeric to p57
on chromosome 11p15 (Lee et
al. 1999; Smilinich et al. 1999). An additional 15% of
patients show LOI of IGF2 (MIM 147470), located in
a second imprinted subdomain 280 kb telomeric to
LQT1 (Weksberg et al. 1993; Steenman et al. 1994).
LOI of LIT1 involves aberrant hypomethylation and ac-
tivation of the normally silent maternal allele. The target
of LOI of LIT1 presumably is p57
, although it is not
clear whether LIT1 serves as a transcriptional repressor
of p57
or as an insulator separating p57
from its
enhancer. Deletion of the differentially methylated re-
gion (DMR) leads to activation of the paternal allele of
, as well as those of Tssc3, Tssc5, Kcnq1, Tssc4,
and Ascl2 (Fitzpatrick et al. 2002). Similarly, targeted
deletion of the LIT1 CpG island on a human paternal
Received July 16, 2004; accepted for publication August 24, 2004;
electronically published September 15, 2004.
Address for correspondence and reprints: Dr. Andrew P. Feinberg,
720 Rutland Avenue, Baltimore, Maryland, 21205. E-mail: afeinberg@
2004 by The American Society of Human Genetics. All rights reserved.
chromosome in chicken DT40 cells leads to activation
of the paternal allele of K
lqt1 and p57
(Horike et
al. 2000). Presumably, the DMR contains elements im-
portant for silencing on the paternal allele. An engi-
neered translocation in the mouse, disrupting the im-
printed cluster with a targeted translocation between
and K
lqt1, results in loss of expression of the
maternal allele of p57
, Tssc3, and Tssc5 (Cleary et
al. 2001), suggesting that there are also elements within
or proximal to LIT1 important for gene activation on
the maternal allele. It should be noted, however, that
there is no mouse model involving LIT1 leading to BWS.
We sought to identify patients with BWS who have
microdeletions on 11p15, since similar studies had clar-
ified the role of imprinting regulatory elements in the
Prader Willi/Angelman syndrome gene region of 15q11-
15q13 (Buiting et al. 1995). To screen for LIT1 dele-
tions, we used real-time quantitative PCR of genomic
DNA for copy number analysis, normalizing to a ref-
erence locus, and combined these efforts with FISH of
metaphase and interphase cells.
Subjects and Methods
Patients with BWS were identified as part of a BWS
registry first established in 1994. Participating families
provided detailed clinical information and written in-
formed consent approved by the respective institutional
review boards. BWS in the registry is defined by a clinical
diagnosis by a experienced physician but requires at least
two of the five most common features: (1) macroglossia,
Page 1
Niemitz et al.: LIT1 Microdeletion in BWS 845
(2) birth weight and length
190th percentile, (3) hypo-
glycemia in the 1st mo of life, (4) ear creases or ear pits,
and (5) midline abdominal wall defects.
Real-Time Karyotyping
Genomic DNA was prepared from peripheral-blood
lymphocytes by standard proteinase K digestion and
phenol extraction (Cui et al. 1998). Genomic copy num-
bers of sequences within K
LQT1 and flanking genes
were measured using quantitative real-time PCR ampli-
fication with Taqman probes. Reactions were performed
using 1# Taqman master mix (ABI), 300 nM each
primer, 200 nM probe, and 10 ng of peripheral white
blood cell genomic DNA in a total volume of 25 ml. All
reactions were performed in triplicate. For each sequence
amplified, triplicate reactions of a no template control
and a standard curve were amplified at the same time.
The standard curve was prepared from normal control
genomic DNA at 100# (100 ng per reaction), 10# (10
ng per reaction), and 1# (1 ng per reaction). Reactions
were run on an ABI 7700 instrument under standard
conditions (50Cfor2min;95C for 10 min; 95Cfor
15 s, 60C for 1 min for 40 cycles). All triplicate cycle
threshold (Ct) values were checked to ensure that they
were within 1 Ct of each other. The log input amount
of the standard curve was plotted versus the output Ct
values; only amplifications that produced a slope of
3.3 to 3.8 were accepted as quantitative. The log
input amount of each sample was calculated according
to the formula , where b is the Y-intercept,(Ct b)/m
and m is the slope. The log input amount was converted
to input amount according to the formula 10^(log input
amount), and triplicate input amounts were averaged
for each sample. The average input amount of each se-
quence amplified was normalized to the average input
amount of peripheral myelin protein 22 (PMP22);
primer and probe sequences for PMP22 were reported
by Wilke et al. (2000). PMP22 is located on chromo-
some 17 and is involved in Charcot-Marie-Tooth syn-
drome, a sensory and motor neuropathy disease unre-
lated to BWS. All primers are listed in the appendix
(online only).
To confirm the deletion localization in lymphoblast cells
derived from patients II-2 and III-4, two-color FISH was
performed using several BAC and PAC clones, including
LQT1 genomic DNA as a probe. The probes were
labeled with digoxigenin-11-UTP (Roche) and biotin-16-
dUTP (Roche), respectively, by nick translation. Probes
were purified by ethanol precipitation, dissolved in 5 ml
of formamide, mixed, and denatured. Hybridization
solution (BSA [Roche]:10# SSC:50% dextran sulfate
[Sigma], 1:2:2) and labeled probes were mixed 1:1,
dropped onto denatured chromosomes, covered with
parafilm, and incubated at 37C for 15 h in a humidified
chamber. After hybridization, the slides were washed se-
quentially at 37C in 50% formamide/2# SSC, 2# SSC,
1# SSC for 15 min each and once in 4# SSC for 5 min.
The slides were immersed in 70 mlof3mg/ml fluorescein
isothiocyanate (FITC)–avidin (Vector Laboratories), and
1.6 mg/ml anti-digoxigenin-rhodamine (Roche), 4# SSC,
and 1% BSA for 45 min at 37C. The slides were then
washed for 5 min each in 4# SSC, 4# SSC containing
0.05% Triton X-100, and then 4# SSC. The slides were
incubated with 70 mlof5mg/ml biotinylated anti-avidin
(Vector Laboratories), 4# SSC, and 1% BSA at 37C for
60 min. After washing, another layer of FITC-avidin was
added for amplification. The slides were washed and
mounted in antifade solution (1% diazabicyclooctane
[Sigma] in glycerol with 10% PBS) containing 0.2 mg/ml
-diamidino-2-phenylindole (Sigma) and 100 mg/ml p-
phenylenediamine (Sigma). Signals were observed with a
Nikon fluorescence microscope. One hundred nuclei and
metaphases were analyzed.
Real-Time Quantitative Analysis of Gene Expression
RNA isolated from primary lymphocytes was con-
verted to cDNA through use of the Superscript II kit
(Invitrogen) according to the manufacturer’s protocol.
A standard curve was constructed from pooled normal
control cDNA. Reactions were performed using 1#
Taqman master mix (Applied Biosystems), 270 nM each
primer, and 60 nM probe in a total volume of 25 ml.
GUS reactions were performed using 24 ng of original
input RNA, and p57
reactions were performed using
192 ng of original input RNA. All reactions were per-
formed in triplicate, including, for each sequence am-
plified, a no-template control. The RT-negative reactions
were used as template for one p57
reaction, to ensure
that no amplification occurred. Reactions were run on
an ABI 7700 instrument according to standard condi-
tions (50Cfor2min;95C for 10 min; 95C for 15 s,
60C for 1 min for 40 cycles). All triplicate Ct values
were checked to ensure that they were within 1 Ct of
each other. For p57
, the average slope of the standard
curve was 3.73, and for GUS, the average slope of the
standard curve was 3.68; both of these are within the
desired quantitative range. Data analysis converting trip-
licate Ct values into average input amount ratios was
performed as described above in the “Real-Time Karyo-
typing” subsection. The SD was, on average, 23% of
the ratio value. A human endogenous control plate (Ap-
plied Biosystems) was used, according to the manufac-
turer’s instructions, to choose a housekeeping gene for
expression normalization in primary lymphocytes.
Page 2
846 Am. J. Hum. Genet. 75:844–849, 2004
We used real-time quantitative PCR of genomic DNA
to screen for microdeletions in BWS. We examined 34
patient samples by this approach. Of these, two patients
had familial BWS, each with at least one fully affected
sib. We detected a microdeletion in one of the familial
cases, as described in detail below. The other familial
case showed evidence of a complex rearrangement (not
discussed here).
At the time of ascertainment, patient III-4 (fig. 1A)
was a 6-year-old boy with hemihypertrophy with asym-
metric enlargement of the right leg and arm, hypospa-
dias, cleft palate, midline abdominal wall defect (dias-
tasis recti and umbilical hernia), characteristic ear pits
and creases, undescended testes, and macroglossia re-
quiring surgery. Two siblings also had BWS: a sister
(patient III-1, fig. 1A) with prenatal overgrowth, ear
creases and pits, and macroglossia requiring surgery;
and a brother (patient III-2, fig. 1A), stillborn at 28 wk,
with prenatal overgrowth and macroglossia. The father
was 37 years old and the mother 36 years old at the
proband’s birth, and both parents showed no signs of
BWS in childhood or later.
The deletion was mapped by real-time karyotyping
with probes spanning K
LQT1 (fig. 2A). The deleted
region of 250 kb removes all of LIT1 and is within
LQT1; the centromeric breakpoint is located be-
tween exons 1b and 1c, and the telomeric breakpoint
is located between exons 11 and 14 (K
LQT1 exon
numbering from GenBank sequence AJ006345). This
deletion was detected in individuals II-2 and III-4; II-2
is the mother of III-4 (fig. 1A), indicating that it had
been transmitted from the mother to the proband and
likely to the other two deceased sibs with BWS as well.
The presence and localization of the deletion was in-
dependently confirmed cytogenetically through use of
two-color interphase and metaphase FISH with BAC
and PAC probes spanning K
LQT1 (fig. 2B). PAC
probes AC002403 and U90095, spanning K
from approximately exon 2a to exon 11, generated one
chromosomal signal in a majority of interphase and
metaphase nuclei in diploid lymphoblast cells derived
from patients II-2 and III-4, whereas flanking probes
AC003693 (PAC) and AC013791 (BAC) generated two
chromosomal signals (fig. 2B).
To determine the identity of the parental allele carrying
the deletion, we performed haplotype analysis, using mi-
crosatellite markers across 11p15 (fig. A [online only]).
Through use of these data, haplotype analysis of the
available individuals placed the deletion on the “ACIL”
haplotype (fig. 1A). Individual II-2 inherited the chro-
mosome carrying this haplotype from her father, indi-
vidual I-2, and passed this haplotype to her son, indi-
vidual III-4, indicating that the deletion was present on
a paternal chromosome in individual II-2 and on a ma-
ternal chromosome in individual III-4. Methylation anal-
ysis of the LIT1 DMR by methyl-sensitive Southern blot-
ting (fig. 1B) was used to confirm the parental origin and
indicated the absence of an unmethylated paternal band
in individual II-2 and the absence of a methylated ma-
ternal band in individual III-4. Methylation analysis of
the H19 DMR by methyl-sensitive Southern blotting (fig.
1B) was used to confirm that the deletion had no effect
on the distal, independently regulated H19/IGF2 cluster
and indicated the normal presence of both parental bands
in all tested individuals.
The patient’s mother inherited the deletion from her
father, and thus we could compare the effect on gene
expression of a maternally inherited deletion with that
of a paternally inherited deletion. If the deletion re-
moved a p57
enhancer, then the patient would be
expected to show reduced expression with no change
in expression in the mother. In contrast, if LIT1 acts as
a silencer—that is, as a repressor of p57
over a dis-
tance—then the paternally inherited allele would be ex-
pected to be activated. To determine the relationship
between the microdeletion and expression of p57
we performed real-time quantitative RT-PCR of p57
(fig. 2C). We could not measure allele-specific expres-
sion of p57
directly, since there were no polymor-
phisms in the exons, introns, or promoter of p57
TSSC3 and TSSC5 are not consistently imprinted in
humans postnatally, so the effect on imprinting of more-
distant genes could not be assessed.
The expression level of p57
was measured in pe-
ripheral blood lymphocyte RNA from individuals III-4
and II-2 and compared with normal age-matched con-
trols. These data indicated that p57
expression is
reduced in the proband (relative expression level 1.2,
versus a mean SD of in age-matched con-7.9 3.8
trols [fig. 2C]). In contrast, expression of p57
normal in the patient’s mother, compared with that in
age-matched controls (fig. 2C). Therefore, the micro-
deletion decreased p57
expression when inherited
maternally but had no effect when inherited paternally,
suggesting a mechanism of enhancer deletion. In addi-
tion, LIT1 itself showed normal expression in the pro-
band but no detectable expression in the proband’s
mother (fig. 2C), consistent with loss of her paternally
inherited copy, which is normally the only active allele.
Since the mother had no growth or developmental ab-
normalities, the absence of LIT1 RNA had no discern-
ible phenotypic effect on her.
In summary, we have described a microdeletion on
11p15 in two related individuals, one in whom the de-
letion is maternally inherited and the other in whom the
Page 3
Niemitz et al.: LIT1 Microdeletion in BWS 847
Figure 1 Haplotype and methylation analysis of LIT1 microdeletion. A, Haplotype mapping using 11p15 microsatellite markers D11S988,
D11S1318, D11S922, D11S2071, which were amplified using FAM-labeled primers and detected using an ABI 3100 capillary electrophoresis
instrument. Haplotypes were constructed using peak size data (see fig. A [online only]). The haplotypes of individuals I-1 and II-3 are inferred.
B, Methylation at LIT1 and H19, assayed by methyl-sensitive Southern blotting using genomic DNA from the indicated individuals. For LIT1,
the upper band (6.0 kb) is methylated and represents the maternal allele, and the lower band (4.2 kb) is unmethylated and represents the
paternal allele. For H19, the upper band (1.8 kb) is methylated and represents the paternal allele, and the lower band (1.0 kb) is unmethylated
and represents the maternal allele. LIT1 shows gain of methylation in II-2 and loss of methylation in III-4. H19 is unaffected.
deletion is paternally inherited. Although the mechanism
of regulation of the imprinted cluster of the genes IGF2
and H19 has been well studied and related to the BWS
phenotype, the regulation and disease-causing mech-
anism of the imprinted cluster of the genes p57
LQT1, LIT1, TSSC3, and TSSC5 is less well under-
stood. In humans, it is clear that inactivating mutations
in p57
cause BWS, and LOI and aberrant methylation
of LIT1 has been associated with a third of all BWS
cases. A number of studies in mice have indirectly shown
that LIT1 plays a role in regulating imprinted expression
of the nearby genes p57
, TSSC3, and TSSC5. In mice,
disruption of the imprinted cluster with a targeted trans-
location between p57
and K
LQT1 results in loss of
expression and loss of imprinting of the genes p57
TSSC3, and TSSC5 (Cleary et al. 2001), indicating that
LQT1 harbors important regulatory elements. How-
ever, knockout of the DMR of LIT1 in mice results in
derepression of nearby imprinted genes and a micro-
somic phenotype when inherited paternally, although
there is no affect on growth or imprinted gene expression
when inherited maternally (Fitzpatrick et al. 2002).
Here, we provide the first human genetic evidence
that the LIT1 domain contains regulatory elements that
play a mechanistic role in the BWS phenotype and reg-
ulates the imprinting and expression of nearby im-
printed genes. This microdeletion provides genetic con-
firmation of the importance of regulation of p57
a distance in the pathogenesis of BWS. The model that
best fits these data is that, in the case of the maternal
deletion, p57
expression is lost because of loss of an
enhancer within or telomeric to LIT1, leading to BWS,
which supports the prediction of an engineered trans-
location in the mouse (Cleary et al. 2001). Consistent
Page 4
Figure 2 Deletion of LIT1 and altered expression of p57
. A, Genomic copy number of sequences in K
LQT1 in individuals II-2 and
III-4 and in four normal control individuals. Genomic DNA was amplified in the presence of a Taqman probe and normalized to PMP22 on
chromosome 17. The X-axis indicates K
LQT1 genomic sequence (GenBank accession number AJ006345), and the Y-axis indicates the relative
copy number of each probed sequence. See the appendix (online only) for primer and probe sequences. B, Two-color FISH using PAC probes
in lymphoblastoid nuclei from patient III-4. Probe AC003693 (blue) generated two chromosome signals in interphase (left) and metaphase
(right) nuclei, whereas probe U90095 (red) generated one chromosome signal in interphase and metaphase nuclei. A pair of spots was scored
as one signal, since it represents the two sister chromatids after S phase. Interphase nuclei and chromosomes were counterstained with DAPI.
One hundred interphase and metaphase nuclei were analyzed, 90 and 85 of which, respectively, showed similar patterns to those described
above. LIT1 is deleted in individuals II-2 and III-4. C, Real-time mRNA expression analysis of p57
and LIT1 in deletion carriers. Values
represented are the average input amount of p57
, normalized to the average input amount of the b-glucuronidase (GUS) gene in triplicate
samples, compared with age-matched normal lymphocyte controls; and the average input amount of LIT1, normalized to the average input
amount of the b-actin gene in triplicate samples, compared with normal lymphoblastoid controls. The housekeeping gene chosen for normalization
in cases was the gene with the least variance among eight control samples. p57
expression is decreased in the proband (III-4), and LIT1
expression is absent in the mother (II-2).
Page 5
Niemitz et al.: LIT1 Microdeletion in BWS 849
with this idea, Diaz-Meyer et al. (2003) found incom-
plete silencing of p57
in several patients with BWS
who had LOI of LIT1, compared with patients without
BWS, although patients with BWS who didn’t have LOI
were not examined in that study.
In addition, absence of an LIT1 transcript, as found
in the proband’s mother, had no phenotypic conse-
quence, indicating that the LIT1 RNA has no significant
physiological function when inherited paternally. The
deletion in this family is also of practical importance
that should be brought to the attention of clinical ge-
neticists performing molecular diagnosis of BWS. Sev-
eral centers worldwide are performing methylation
analysis for BWS, the results of which will be abnormal
for these individuals. However, unlike LOI of LIT1, in
which the recurrence risk and transmissibility are un-
known, definitive counseling can be provided to patients
with the deletion by using methylation analysis and ei-
ther digital karyotyping or FISH with the appropriate
probes. A mother carrying the deletion would have a
50% risk of transmission to subsequent offspring, and
similar counseling could be provided to the probands
as well.
We thank the families who participated in the study and
Marcia Cruz-Correa for preparing the Spanish language con-
sent. We thank Shirley Tilghman for many helpful conversa-
tions and discussion of unpublished data in the mouse. This
work was supported by National Institutes of Health grant
CA54358 (to A.P.F.) and by the Birth Defects March of Dimes
Electronic-Database Information
The accession number and URLs for data presented herein
are as follows:
GenBank, (for
LQT1 genomic sequence [accession number AJ006345])
Online Mendelian Inheritance in Man (OMIM), http://www (for BWS, p57
, LIT1,
LQT1, and IGF2)
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    • "Familial or de novo deletions in BWS affecting the ICR1 or ICR2 on chromosome 11p15 are rare findings. Only four maternal deletions affecting the ICR2 have been reported so far10111213 However, in one case the deletion includes the CDKN1C gene, explaining the BWS phenotype because of the lack of the maternal CDKN1C transcript. All these ICR2 deletions are large in size spanning 198- 900 kb genomic DNA. "
    [Show abstract] [Hide abstract] ABSTRACT: Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder with a variable clinical phenotype caused by deregulation affecting imprinted genes in the chromosomal region 11p15. Alterations of the imprinting control region 1 (ICR1) at the IGF2/H19 locus resulting in biallelic expression of IGF2 and biallelic silencing of H19 account for approximately 10% of patients with BWS. The majority of these patients have epimutations of the ICR1 without detectable DNA sequence changes. Only a few patients were found to have deletions. Most of these deletions are small affecting different parts of the ICR1 differentially methylated region (ICR1-DMR) removing target sequences for CTCF. Only a very few deletions reported so far include the H19 gene in addition to the CTCF binding sites. None of these deletions include IGF2. Case presentation A male patient was born with hypotonia, facial dysmorphisms and hypoglycemia suggestive of Beckwith-Wiedemann syndrome. Using methylation-specific (MS)-MLPA (Multiplex ligation-dependent probe amplification) we have identified a maternally inherited large deletion of the ICR1 region in a patient and his mother. The deletion results in a variable clinical expression with a classical BWS in the mother and a more severe presentation of BWS in her son. By genome-wide SNP array analysis the deletion was found to span ~100 kb genomic DNA including the ICR1DMR, H19, two adjacent non-imprinted genes and two of three predicted enhancer elements downstream to H19. Methylation analysis by deep bisulfite next generation sequencing revealed hypermethylation of the maternal allele at the IGF2 locus in both, mother and child, although IGF2 is not affected by the deletion. We here report on a novel large familial deletion of the ICR1 region in a BWS family. Due to the deletion of the ICR1-DMR CTCF binding cannot take place and the residual enhancer elements have access to the IGF2 promoters. The aberrant methylation (hypermethylation) of the maternal IGF2 allele in both affected family members may reflect the active state of the normally silenced maternal IGF2 copy and can be a consequence of the deletion. The deletion results in a variable clinical phenotype and expression.
    Full-text · Article · Dec 2015 · BMC Medical Genetics
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    • "Distinct epigenetic defects have been linked to separate hereditary growth anomalies, providing evidence for a broad regulatory role of DNA methylation on body growth. The Beckwith-Wiedemann syndrome (130650) is caused by deregulation of imprinted genes within the 11p15 chromosomal region, i.e., KIP2, H19 and LIT1, whether alone or as interacting regulatory units (Niemitz et al. 2004). Hypermethylation at the 11p15 telomeric imprinting control region (ICR1), are observed in about 5 to 10% of affected patients (see below for opposite epigenetic changes in Silver-Russel patients). "
    [Show abstract] [Hide abstract] ABSTRACT: Genome-wide SNP analyses have identified genomic variants associated with adult human height. However, these only explain a fraction of human height variation, suggesting that significant information might have been systematically missed by SNP sequencing analysis. A candidate for such non-SNP-linked information is DNA methylation. Regulation by DNA methylation requires the presence of CpG islands in the promoter region of candidate genes. Seventy two of 87 (82.8%), height-associated genes were indeed found to contain CpG islands upstream of the transcription start site (USC CpG island searcher; validation: UCSC Genome Browser), which were shown to correlate with gene regulation. Consistent with this, DNA hypermethylation modules were detected in 42 height-associated genes, versus 1.5% of control genes (P = 8.0199e−17), as were dynamic methylation changes and gene imprinting. Epigenetic heredity thus appears to be a determinant of adult human height. Major findings in mouse models and in human genetic diseases support this model. Modulation of DNA methylation are candidate to mediate environmental influence on epigenetic traits. This may help to explain progressive height changes over multiple generations, through trans-generational heredity of progressive DNA methylation patterns.
    Full-text · Article · Jun 2014
    • "Thus, it is uncommon that in the placental lesions here summarized, appropriate genetic studies are undertaken to rule out the syndrome. It is a syndrome whose gene appears to be located on 11p15 and has variability with respect to imprinting domains and mutations of p57(KIP2) (see Niemitz et al. 2004 ) . Deletions had not been recognized until their case was described; thus, refi ned genetic scrutiny would be in order also for the chorangiomas that, after all, also represent a form of neoplastic tendency as is the case with BWS. "
    [Show abstract] [Hide abstract] ABSTRACT: With rare exceptions, vascular tumors are the only benign tumors of the placenta. Tumors designated as chorioangiomas, chorangiomas, fibroangiomyxomas, fibromas, and the many other names that have been applied in the past are essentially similar, relatively common neoplasms of the placenta. Three large reviews have been published that bring together most of the literature. DeCosta et al. (1956) found about 250 case reports and listed all the synonyms applied previously. They also made reference to the frequency of hydramnios and associated fetal angiomas. Fox (1967), who also reviewed the often confusing nomenclature, indicated that Clarke described the first such tumor in 1798. Since then, the review by Siddall (1924) encompassed 130 cases, that by Marchetti (1939) comprised 209 cases, and Fox traced another 127 cases. Fox accounted for 344 published cases and gave incidence figures of one in 9,000 to one in 50,000 placentas. When careful study of placentas is undertaken, the real prevalence may be as high as one in 100 pregnancies, according to some authors (e.g., Wentworth 1965, who found one in 77); although in our experience, this number is somewhat excessive. Wallenburg (1971) provided 13 new cases and summarized publications between 1939 and 1970. His reported incidence in consecutively collected placentas was one in 117. These authors provided an extensive literature documentation that would be redundant to repeat. Bashiri et al. (2002) found a significant risk of preterm delivery in patients with chorangiomas. Soma et al. (1991) found that the tumor existed in 0.2% of placentas in Japanese women but was more common (2.5–7.6%) in the high altitude population of Nepal (Soma 2001). This is similar to the higher frequency of chorioangioma observed in placentas of women living at altitude by Reshetnikova et al. (1996). We have seen chorioangiomas associated with chronic vascular thrombi and elevated NRBCs in the fetal circulation. Thus, a hypoxic stimulus is inferred to lead to excessive villous capillary proliferative stimulation. While still speculative, such angiogenesis may well be regulated by such vascular growth factors as demonstrated to occur in the placenta by Jackson et al. (1994). A more detailed consideration of the placental villous adaptation to hypoxia can be found in the contribution by Kaufmann et al. (1993), and the paper by Kadyrov et al. (1998) provided information on how anemic women produce increased placental angiogenesis in early development. The control of angiogenesis is complex, but it is an essential aspect of placentation and regulation during anemia, preeclampsia, and other pathologic states in pregnancy. There are numerous factors now being explored, and many have significant impact on the villous vascularization. A detailed review was provided by Sherer and Abulafia (2001) that is too complex, however, for the brief consideration possible in this chapter. Guschmann (2002, 2003) and his colleagues in Berlin (Guschmann et al. 2003) have described various angiogenesis factors in chorangiomas. It was their experience that high expression of angiopoietin-1 and 2 and their receptors was demonstrated in chorangiomas, while VEGF was uniform with the normal villi, but variability existed. Further remarkable in their series was that 72% of accompanying babies were of female gender, and tumors occurred much more commonly in the first pregnancy. North et al. (2001) studied immunoreactivity for a variety of antigens in chorangiomas and juvenile angiomas. Thus, FcgammaRII, Lewis Y antigen, merosin, and GLUT1 were found to be highly expressed in the small placental vessels and angiomas, but not in control blood vessels or those of granulomas etc.
    No preview · Chapter · Jan 2012
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