Angelman Syndrome 375

Angelman Syndrome
L M Bird, Rady Childrens Hospital and University of
California, San Diego, CA, USA
2009 Elsevier Ltd. All rights reserved.

Introduction
Most autosomal genes are expressed from both parental copies (biallelic expression), regardless of the parental origin. A small number of genes are expressed
from only one parents allele, a phenomenon known as
genomic imprinting. Angelman syndrome (AS) is one
of the most well-understood syndromes of genomic
imprinting. AS maps to the imprinted gene cluster on
chromosome 15q11q13 and is due to defective
expression of the maternally inherited ubiquitin protein ligase 3A gene (UBE3A/E6-AP). There are at least
four molecular classes of AS, demonstrating the genetic
complexity of this disorder. Though AS is a monogenic
disorder, it is a prototype for the so-called mixed epigenetic and genetic and mixed de novo and inherited
(MEGDI) model of disease. Herein follows a summary of the progress made to date in elucidating the
mechanisms of imprinting in AS.

Clinical Background
The clinical features of AS are microcephaly, functionally severe mental retardation, ataxic gait, seizures, and
electroencephalographic abnormalities. The behavioral
profile of AS includes exceptionally happy disposition
with episodes of laughter; excessive mouthing of objects, drooling, and tongue thrusting; easy excitability
and hypermotoric activity; reduced need for sleep, with
sleep disturbance; and an affinity for water.
Seizures begin in infancy or early childhood in the
majority of patients, and often show attenuation in
adolescence. A wide variety of seizure types have been
reported. Movement disturbances (tremors, jerkiness,
poor coordination) contribute to the delayed acquisition of motor skills (sitting after 12 months; walking
between 2 and 6 years). The incidence of nonambulation is said to be 10%, but this may no longer be true
in the modern era of earlier diagnosis and prompt
intervention. The early institution of physical therapy
may change the natural history of scoliosis (said to
occur in 50%) by improving truncal tone.
Virtually all AS patients exhibit a short attention
span, and most are hypermotoric. Some aggressive,
unwanted behaviors are displayed by the majority of
patients, including biting, pinching, hair-pulling, and
grabbing. Rarely are these behaviors intended to
cause harm; they usually result from easy excitability,

poor control over movements, reduced repertoire of

need expression, and occasionally frustration over an
inability to communicate effectively. Paroxysms of
laughter are said to occur in AS, but laughter is rarely
unprovoked, though often inappropriate to the triggering stimulus. A happy disposition characterizes
most children, but irritability is common in infancy.
Gastrointestinal difficulties such as gastroesophageal
reflux may contribute to this irritability. AS patients
have an apparent reduced need for sleep (56 h per
night) and many have long or frequent periods of
wakefulness during the night. With behavior modification and medication, these difficulties can be overcome in most patients, and sleep patterns improve
with age.
Cognitive performance is usually in the range of
severe functional impairment. The combination of
deficits exhibited by individuals with AS make the
commonly used developmental assessment tools difficult to apply, and these tests probably underestimate
the abilities of AS children. Receptive language is far
superior to expressive language, which is often completely absent. Nonverbal communication using a
variety of systems (picture exchange cards; communication devices) is possible in a substantial proportion
of AS patients. Poor fine motor coordination usually
precludes the use of sign language.
AS adults are not able to live independently, but
most are able to using feeding utensils and perform
some household tasks. Dressing skills are dependent
on the degree of fine motor difficulty. Daytime continence is possible with prompted voiding and habit
training. Life expectancy appears to be normal.

Molecular Genetics of AS
Failure of maternally inherited UBE3A to be transcribed and translated into a functional protein causes
AS. Four molecular mutation classes of AS have been
defined: deletion, uniparental disomy (UPD), imprinting defect, and UBE3A mutation.
Deletion

Approximately 65% of AS cases exhibit a de novo

(
4 Mb) microdeletion of chromosome 15q11q13.
Two major classes of deletions exist, one from breakpoint 1 (BP1) to breakpoint 3 (BP3) (class I) and the
other from breakpoint 2 (BP2) to BP3 (class II) (see
Figure 1). Rarely, patients may have a larger deletion
that extends beyond the boundaries of BP1 and BP3 in
one or both directions. Deletions are apparently
mediated by homologous misalignment and meiotic
recombination between low-copy-number repeats

376 Angelman Syndrome

AB
A
G RB
AB 3
AR
G
AB A5
AR
G
3
P
(O
CA
HE 2)
RC
HE 2
RC
2du
p

0C

P1
AT

A
E3

snoRNAs

UB

IC
-A
IC S
-P
W
SN S
RP
N

M
KR
M N3
AG
E
ND L2
N

HE

HE

RC

RC

2-

2-

du

du

SNRPN sense/UBE3A antisense transcript

Cen

Tel
BP1

BP2

BP3

Figure 1 Genomic organization of human chromosome 15q11q13. Blue loci are paternally transcribed, pink loci are maternally
transcribed, and the gray loci are biparentally expressed. Arrows indicate direction of transcription. Black ovals denote bipartite imprinting
center (IC-AS, IC-PWS). Cen, centromere; Tel, telomere; BP1, BP2, BP3, common break points. Adapted from Nicholls RD and Knepper JL
(2001) Genome organization, function and imprinting in PraderWilli and Angelman syndromes. Annual Review of Genomils and Human
Genetics 2: 153175.

(duplicons) that have been identified in proximal and

distal 15q11q13. These duplicons arose with the
amplification of an ancestral gene, HERC2. Duplicons having 9099% identity to the first 79 exons of
HERC2 are found in at least nine copies in 15q11
q13 as well as two copies on chromosome 16. There is
one reported case of maternal germ line mosaicism
producing familial recurrence of a deletion.
Uniparental Disomy

Paternal UPD accounts for approximately 5% of cases

of AS, and in almost all cases, the UPD is isodisomic.
The most likely origin of this event is maternal nondisjunction producing a monosomy 15 conception, with
postzygotic rescue by duplication of the paternal chromosome 15. As in the deletion cases, this class of AS
represents de novo mutational events and has a very
low risk for recurrence.
Imprinting Defect

In approximately 10% of cases, an imprinting defect

underlies AS. In this class of AS, a paternal imprint
is erroneously assigned to the maternally inherited
allele. Two types of imprinting defects are known:
those due to a submicroscopic deletion of the imprinting center (IC) and those with no detectable
mutation. Most submicroscopic IC deletions are
familial, carrying a 50% risk for recurrence. Thus
far all imprinting defects with undetectable mutations
have been sporadic events. They are presumed to
result from failure to establish or maintain the
imprint during oogenesis, due to a stochastic event
or perhaps (as yet unknown) environmental factors.
UBE3A Mutation

UBE3A was initially discarded as a potential candidate for the AS gene because it appeared not to be
imprinted when studied in lymphocytes and fibroblasts, and its widespread expression ran counter to
expectation since the AS phenotype is exclusively
neurological. Establishing brain-only imprinting
of Ube3a in mice resurrected UBE3As status as a

candidate gene for AS. Analysis of UBE3A in AS

patients with biparental contribution to 15q11q13
and no imprinting abnormalities showed point mutations in several unrelated patients, identifying it as the
gene responsible for the AS phenotype. Intragenic
UBE3A mutations (insertion, deletion, nonsense, missense, and splice site mutations) cause approximately
10% of cases of AS. Substantial portions of UBE3A
mutations are inherited from the mothers paternally acquired allele. In this circumstance, a 50%
recurrence risk pertains.
Negative Molecular Studies

In addition to the four molecular classes described,

approximately 10% of cases of AS have the clinical
profile but no discernible molecular defect. Wholegene or large intragenic deletions of UBE3A are not
detected by the clinically available diagnostic tests
(DNA methylation analysis of chromosome 15q11
q13 and UBE3A sequence analysis). Intragenic deletions have been reported in two families, but do not
appear to be the explanation for the bulk of cases
of AS with negative molecular studies. While some
patients with the AS phenotype and negative molecular studies may represent misdiagnoses, it is likely that
other molecular mechanisms affecting UBE3A expression will be found to explain this class of patients.

Molecular Biology of AS
UBE3A spans 120 kb of genomic DNA. Mutations
have been detected throughout all regions of the gene,
and there do not appear to be mutational hot spots.
Sixteen exons have been identified; additional exons
at the 50 end of the gene are possible, as this region
displays alternative splicing. Transcription of UBE3A
occurs in a telomeric-to-centromeric direction. RNA
transcripts of 56 kb include approximately 2 kb of
30 -untranslated region (UTR) sequence. There are at
least seven mRNA species produced by alternative
splicing at exons 5 and 6, at the 50 end, and possibly
at the 30 end. The various transcripts produce three

Angelman Syndrome 377

isoforms of UBE3A protein. Isoforms II and III have

20 and 23 additional amino acids, respectively, at the
N-terminus, compared with isoform I. The function of
the different isoforms of UBE3A remains unknown.
There are tissue-specific variations in RNA splicing
and isoform predominance, but the significance of
these differences is unclear.
UBE3A encodes an E3 ubiquitin ligase, E6-AP (E6associated protein). Though first characterized by its
interaction with the E6 protein of papillomaviruses
to promote degradation of p53, E6-AP does not
maintain a stable association with p53. It participates
in the ubiquitin pathway of protein degradation in
proteosomes. In this pathway, ubiquitin is covalently
attached to one or more lysine residues of proteins
destined for destruction. Ubiquitination involves a
three-step process (activation of ubiquitin by an E1
enzyme, transfer to an E2 conjugating enzyme, and
covalent ligation of ubiquitin to the protein substrate
by an E3 ligase), the third step of which is deficient in
AS. The C-terminus of UBE3A is a functionally important and highly conserved domain that is shared by
a family of proteins (hect domain, so named because it
is homologous to the E6-AP carboxy terminus). The
last six amino acids of the E6-AP C-terminus are
essential for activity in vitro. It is unknown how substrate specificity is determined. E6-AP is found in all
tissues that have been studied.

Clinical Difference in Classes of AS

Clinical differences between the molecular classes
of AS have been recognized. As a group, patients
with deletions tend to have a more severe phenotype
(later onset of independent walking, earlier onset and
increased severity of seizures, and complete absence of
speech) compared to patients with UPD, imprinting
defect, or UBE3A mutation. Though speech is usually
absent in deletion AS patients, use of up to 20 words
is reported in AS patients with other molecular classes
of AS. The contribution of other genes in the deleted
region to the increased phenotypic severity is not clear.
Three genes for g-aminobutyric acid (GABA) receptor
subunits (GABRB3, GABRA5, and GABRG3) are
located telomeric of UBE3A and are contained within
the common class I and class II deletions. Though these
genes show biallelic expression, a role for them in the
genesis of epilepsy in AS has not been excluded.
Hypopigmentation occurs in some AS deletion
patients. The (unimprinted) P gene located telomeric
within the commonly deleted region is responsible
for autosomal recessive oculocutaneous albinism
type 2 (OCA2). Individuals with AS and OCA2
have been reported, the mechanism being a maternal
chromosome deletion and paternal P gene mutation.

Semidominant behavior of the P gene product

(expression of a hypomorphic allele) has been offered
as a potential explanation for the hypopigmentation
seen in AS deletion patients. However, hypopigmentation is reported in patients with other classes of AS,
including siblings with a maternally inherited intragenic deletion of exons 816 of UBE3A, so the contribution of the P gene to hypopigmentation remains
speculative.
Within the deletion class of patients, those with
larger class I deletions have lower cognitive scores
and are more likely to merit a comorbid diagnosis of
autism. Patients with atypical (larger) deletions are
usually lower functioning.

Mechanisms of Genetic Imprinting

Genetic imprinting confers functional differences
onto the genome such that expression of imprinted
genes occurs only from the father or the mother. The
mechanisms by which an imprint is established in
the germ line, maintained during development and
postnatal life, and reversed in the germ line during
the subsequent generation are unknown. Additional
complexities, such as tissue specificity of imprinting and changes in imprint with age, remain to be
elucidated.
Mechanisms to control gene expression include
insulators (DNA sequence elements that prevent interaction between nearby chromatin domains or prevent
the spread of heterochromatin); transcriptional
enhancer competition (promoters of linked imprinted
genes competing for access to enhancers); modification of chromatin structure by histone acetylation,
phosphorylation, and methylation; and DNA methylation. Each of these mechanisms provides a layer of
information beyond what is contained within the
nucleotide sequence, and thus contributes to the epigenotype. Imprinted genes cluster together in specific
areas of the genome, an observation that suggests
coordinate regulation by a regional element, known
as the imprinting control region (ICR).
DNA methylation, the modification of DNA by the
addition of a methyl group to the cytosine base of
a CpG dinucleotide, is the most well studied of these
epigenetic mechanisms. DNA methylation occurs in
most, but not all, imprinted genes. Loss of DNA methylation occurs during a specific period of germ cell development, and is thought to represent erasure of the
imprint from the previous generation. Reacquisition of
DNA methylation occurs differentially during spermatogenesis and oogenesis, conferring the parent-oforigin specific imprint or epigenotype. It is not clear
whether DNA methylation establishes the imprint or
maintains it, or both.

378 Angelman Syndrome

Less is know about control of gene expression

through covalent modification of histones and their
association with DNA. In general, acetylation of
histones H3 and H4 is associated with increased gene
accessibility (and therefore increased expression).
Methylation of Lys4 of H3 correlates with active gene
expression; methylation of Lys9 of H3 usually accompanies gene silencing. These chemical modifications of
histones attract effector proteins that apparently mediate the increased or decreased gene activity. It is not
clear if DNA methylation directs the histone modifications, or if histone modification drives DNA methylation; it is possible that reciprocal interactions
reinforce the effect of each.

Imprinting of the PraderWilli Syndrome/

AS Region
Both PraderWilli syndrome (PWS) and AS are caused
by defects of the imprinted gene cluster on chromosome 15q11q13 (see Figure 1). Loss of expression of
maternally derived UBE3A causes AS, with the clinical phenotype as described in the preceding sections.
Loss of expression of paternally derived gene(s) from
15q11q13 causes PWS. PWS is characterized by hypotonia and failure to thrive as a neonate, small hands and
feet, short stature, hypogonadism, childhood-onset
hyperphagia and obesity, and cognitive impairment.
Whether a single gene or several genes are required
to produce the PWS phenotype is still a matter of
debate; that no PWS patient with a single gene defect
has been reported suggests that PWS is truly a contiguous gene syndrome.
Differential methylation of chromosome 15q11
q13 has been thoroughly studied. Whether methylation directly or indirectly effectuates the imprint of
genes within the region continues to be argued and
investigated. Differential methylation provides the
basis for the diagnostic testing used to confirm a
suspected diagnosis of AS or PWS. The highly methylated maternal chromosome 15q11q13 region can be
distinguished from the (largely) unmethylated paternal contribution by Southern blot analysis or polymerase chain reaction (PCR) assay of the promoter
region of SNRPN. Maternal-only contribution (due
to paternal deletion, maternal UPD, or imprinting
defect) is diagnostic for PWS. Exclusively paternal
contribution is diagnostic for AS. A normal methylation profile does not rule out AS, however, since a
substantial fraction of AS is due to maternally inherited UBE3A mutations.
The 15q11q13 cluster is under the bidirectional
control of the imprinting center (IC), the designation
for the imprinting control region in this area. The
IC was defined by the identification of small submicroscopic deletions in a subgroup of PWS and AS

multiplex families with biparental inheritance yet

uniparental imprint. The IC is thought to regulate
in cis the establishment and maintenance of the
imprint for the entire cluster. The IC has a bipartite
structure, the PWS-IC and the AS-IC. All AS patients
with IC deletions are missing the AS-IC (880 bp
located 35 kb centromeric of PWS-IC). The function
of the PWS-IC is to establish and maintain paternal
gene expression. During oogenesis, the AS-IC functions to negatively regulate the PWS-IC (through
CpG methylation) and prevent the paternal imprint
from being established. Deletion of the AS-IC produces a paternal imprint of the entire 15q11q13
region; when this is transmitted through the maternal germ line, AS results. A unique inversion case has
shown that the PWS-IC and AS-IC must be closely
and correctly related in order for the maternal
imprint to be established.
MKRN3, NDN, and SNURF-SNRPN are expressed
only from the paternal chromosome, where their promoter regions are unmethylated. MAGEL2 is expressed only from the paternal chromosome, but its
methylation status has not been clarified. Between
SNURF-SNRPN and UBE3A, there are more than
70 snoRNA genes. These are noncoding genes that
produce small nucleolar RNAs, the main function
of which is to modify ribosomal RNA. Though not
imprinted directly by methylation, these snoRNAs
are imprinted indirectly because they are processed
from the paternally expressed SNURF-SNRPN sense/
UBE3A antisense transcript (discussed in the next section), which is under the control of methylation.
In sporadic imprinting defect cases of AS, the maternal grandfathers and maternal grandmothers chromosomes are equally likely to harbor the unmethylated
paternal imprint, suggesting that erasure of the grandmaternal methylation imprint occurs normally, followed by failure to establish (in the case of the
grandpaternal chromosome) or reestablish (in the
case of the grandmaternal chromosome) the correct
maternal imprint.
Much of what we know about methylation status
and imprinting of the chromosome 15q11q13
region comes from investigation of the orthologous
region on mouse chromosome 7C. However, important differences exist. The Frat3 gene is an evolutionarily younger gene which has joined the mouse PWS/
AS region (by retrotransposition) and has acquired
the differential methylation and expression of paternally expressed genes in the region. There is no homolog to Frat3 in the human chromosome 15q11q13
region. Transgenic studies in which human elements
of the PWS/AS region are inserted in the mouse have
shown that both the positive and negative regulatory
elements of the imprinting machinery have diverged.
The mouse equivalent of the human AS-IC has yet to

Angelman Syndrome 379

be identified. Elucidating the mechanism of mouse

PWS/AS region imprinting is likely to yield important
insights, but this information may not be directly
applicable to human UBE3A imprinting.
In addition to methylation, histone modifications
play a role in establishing and maintaining the imprint.
Hyperacetylation of histones H3 and H4, a modification usually signifying gene activation, is found at the
PWS-IC on the paternal allele. Methyl-Lys4 histone
H3, which is typically found at transcriptionally active
loci, associates with PWS-IC and the promoters of
SNRPN and NDN on the paternal allele. DimethylLys9 histone H3, which is generally found in inactive
or heterochromatic regions, associates with the PWSIC on the maternal chromosome.

regulator of, Ube3a. Using a mouse model of AS

generated by targeted disruption of exons 12 and 13
of Ube3a, Landers et al. observed that maternal transmission of the defective allele upregulated expression
of Ube3a-as from the paternal allele. This evidence
suggests that Ube3a expression, rather than being
regulated by Ube3a-as, modulates the levels of the
Ube3a-as and that this interaction occurs in trans.
The mechanism of this modulation is unknown.
Investigating the directionality of the interaction
between UBE3A and UBE3A-AS in the human
brain will be difficult given the scarcity of this
resource.

Gene Repression of UBE3A

UBE3A imprinting is tissue specific, in contrast to

most other imprinted loci in the 15q11-q13 region.
In the brain, there is preferential expression of
UBE3A from the maternal allele, but a small amount
of residual transcription (10%) from the paternal
allele occurs. Another gene, ATP10C, is maternally
expressed in a tissue-specific manner, but so far has
not been shown to contribute to the AS phenotype.
The tissue-specific imprinting of UBE3A appears
to be region specific, with the imprinted expression
pattern being found in the hippocampus and cerebellum, and somewhat in the cerebral cortex. This
regional specificity has been shown to be due to
lineage specificity: UBE3A is expressed exclusively
from the maternal allele only in neurons, and is
biallelically expressed in glial cells and fibroblasts.
Because the hippocampus and cerebellum are neuronrich regions, these regions exhibit the imprint most
strikingly.
The molecular basis of this neuron-specific imprinting is unknown. Two hypotheses have been put forward: (1) the epigenetic marks of neurons are the same
as those in other tissues, but are interpreted differently
by the neuronal transcription machinery; or (2) a specific additional epigenetic mark, a secondary imprint,
is acquired during neuronal differentiation.

The IC is believed to regulate the imprint of 15q11q13

through establishing or maintaining the methylation
profile of the region. However, no site of differential
methylation has been reported within the UBE3A gene
or its vicinity. Though an as-yet-undiscovered site
of allele-specific methylation in or around UBE3A
remains a formal possibility, other mechanisms for
imprint regulation are being proposed and evaluated.
These include enhancer competition, chromatin state
modification, and expression competition by antisense RNA. At present, there is no evidence for chromatin state modification by histone acetylation or
methylation. The expression competition model proposes that the IC controls the methylation of an
imprintor gene (distinct from the IC). The imprintor
gene would be paternally expressed (in a tissuespecific manner) and would compete out expression
of UBE3A.
There is some evidence to support the expression
competition model. A large (>500 kb) transcript
oriented in an antisense manner and spanning the
30 half of UBE3A, as well as the region downstream
of UBE3A, has been identified. This antisense transcript (UBE3A-AS) is expressed only from the paternal allele in the brain, is not expressed in tissues
with biallelic UBE3A expression, and is under the
control of the PWS-IC. In this model, UBE3A-AS is
the direct target of the IC and is imprinted primarily
(in brain), and UBE3A is secondarily imprinted (in
brain) through a repression mechanism. Based on
other examples of imprinting regulation by antisense
transcripts (e.g., XIST, IGF2R), UBE3A-AS is presumed to silence UBE3A by annealing in cis to the
sense promoter. However, the general concept of cis
antisense regulation of neighboring imprinted genes
remains controversial because of conflicting evidence.
Recent evidence from the mouse indicates that
Ube3a-as may be regulated by, rather than being a

Tissue-Specific Imprinting

Summary
AS is a unique neurobehavioral disorder due to defective expression of maternally inherited UBE3A. The
complex mechanisms of how the UBE3A imprint is
established, maintained, and reversed remain to be
elucidated, as does the mechanism of tissue specificity. UBE3A repression apparently does not involve
differential methylation, but possibly is mediated by
expression competition from an antisense transcript.
See also: PraderWilli Syndrome; UbiquitinProteasome
System and Plasticity.

380 Angelman Syndrome

Further Reading
Boyes L, Wallace AJ, Krajewska-Walasek M, et al. (2006) Detection of a deletion of exons 816 of the UBE3A gene in familial
Angelman syndrome using a semi-quantitative dosage PCR based
assay. European Journal of Medical Genetics 49: 472480.
Clayton-Smith J and Laan L (2003) Angelman syndrome: A review
of the clinical and genetic aspects. Journal of Medical Genetics
40: 8795.
Fridman C, Hosomi N, Varela MC, et al. (2003) Angelman
syndrome associated with oculocutaneous albinism due to an
intragenic deletion of the P gene. American Journal of Medical
Genetics 119A: 180183.
Guerrini R, Carrozzo R, Rinaldi R, et al. (2003) Angelman syndrome: Etiology, clinical features, diagnosis, and management
of symptoms. Pediatric Drugs 5: 647661.
Horsthemke B and Buiting K (2006) Imprinting defects on human chromosome 15. Cytogenetic and Genome Research 113: 292299.
Jiang Y, Bressler J, and Beaudet AL (2004) Epigenetics and human
disease. Annual Review of Genomics and Human Genetics 5:
479510.
Jiang Y, Tsai T, Bressler J, et al. (1998) Imprinting in Angelman
and PraderWilli syndromes. Current Opinion in Genetics &
Development 8: 334342.
Johnstone KA, DuBose AJ, Futtner CR, et al. (2006) A human
imprinting centre demonstrates conserved acquisition but diverged

maintenance of imprinting in a mouse model for Angelman

syndrome imprinting defects. Human Molecular Genetics 15:
393404.
Kishino T (2006) Imprinting in neurons. Cytogenetic and Genome
Research 113: 209214.
Landers M, Calciano MA, Colosi D, et al. (2005) Maternal disruption of Ube3a leads to increased expression of Ube3a-ATS in
trans. Nucleic Acids Research 33: 39763984.
Lossie AC, Whitney MM, Amidon D, et al. (2001) Distinct phenotypes distinguish the molecular classes of Angelman syndrome.
Journal of Medical Genetics 38: 834845.
Nicholls RD and Knepper JL (2001) Genome organization, function and imprinting in PraderWilli and Angelman syndromes.
Annual Review of Genomics and Human Genetics 2: 153175.
Nicholls RD, Saitoh S, and Horsthemke B (1998) Imprinting in
PraderWilli and Angelman syndromes. Trends in Genetics 14:
194200.
Rougeulle C and Lalande M (1998) Angelman syndrome: How
many genes to remain silent? Neurogenetics 1: 229237.
Sahoo T, Peters SU, Madduri NS, et al. (2006) Microarray based
comparative genomic hybridization testing in deletion bearing
patients with Angelman syndrome: Genotypephenotype correlations. Journal of Medical Genetics 43: 512516.
Soejima H and Wagstaff J (2005) Imprinting centers, chromatin
structure, and disease. Journal of Cellular Biochemistry 95:
226233.