Imprinting Diseases

Prader–Willi syndrome (PWS) and Angelman
syndrome (AS) are two distinct neurogenetic
developmental disorders that result from
different genetic lesions in a 3–4 Mb contiguous
region of human chromosome 15 (15q11–
13). This region is imprinted, i.e., genes on the
maternal or the paternal allele only are expressed.

Two syndromes associated with the same chromosomal region

Prader–Willi syndrome is characterized by
neonatal muscular weakness and feeding difficulties,
followed in early childhood by reduced
or lack of satiation control leading to massive
obesity in many patients. Several other, variable
features occur, such as mental retardation,
characteristic facial features, short stature, hypopigmentation,
behavioral problems, and
other findings. In Angelman syndrome the
developmental retardation is usually very
severe. Nearly total lack of speech development,
an abnormal electroencephalogram with tendency
to seizures, and hyperactivity are almost
always present.

Parental origin of the deletion

PWS results when the deleted chromosome involves
the chromosome 15 of paternal origin
(loss of one paternal allele 2 in the
diagram of a Southern blot on the left). AS results
when the deletion involves the chromosome
15 of maternal origin (loss of one maternal
allele 1 in the scheme on the right).

Uniparental disomy

Uniparental disomy (UPD) is the presence of
two chromosomes or genes from the same
parent. The diagram of a Southern blot shows
two different types of UPD in PWS: isodisomy
and heterodisomy. In isodisomy the two parental
alleles are identical (two maternal alleles 1
shown in the diagram). In heterodisomy the
two alleles are of the same parental origin, but
differ

Parent-of-origin deletion and uniparental disomy

A deletion and uniparental disomy have the
same functional result, i.e., loss of the genetic
activity of one parental allele. The frequency of
a deletion is about the same for PWS and AS
(70% each), whereas the frequency of UPD
differs considerably: 29% in PWS, 1% in AS.

Chromosomal region 15q11–13 and imprinting center

Five genes known to date are transcribed from
the paternal allele only, not from the maternal
allele where they are constitutively repressed
(blue squares). From the more distal gene
UBE3A (a ubiquitin-protein ligase E3) only the
maternal allele is transcribed. About 25% of
cases of Angelman syndrome are caused by
deletion or mutation of this gene. The breakpoints
of the common large deletions occur predominantly
in three breakpoint cluster regions.
The imprinting center (IC) was originally defined
by small deletions outside of the known
imprinted genes. About 1% of patients with
PWS and 4% with AS have imprinting center defects.
The imprinted region on 15q11–13 shows
a difference in methylation pattern between the
maternal and the paternal allele. This is the
basis of a diagnostic test.
(Data in E. kindly provided by Dr. Karin Buiting).
Other imprinted chromosomal regions are also
associatedwithhumandiseases, e.g.,Beckwith–
Wiedemann syndrome and some patients with
Russell–Silver syndrome, among others.

Karyotype – Phenotype Correlation

Autosomal Trisomies
A trisomy (the presence of three homologous
chromosomes instead of the usual two) arises
prezygotically during meiosis due to faulty distribution
(nondisjunction) of a chromosome
pair. Itmay also arise after fertilization (postzygotic)
during somatic cell division (mitosis); in
this case, trisomy is present in a certain proportion
of cells (chromosomal mosaicism). Trisomy
leads to a phenotype characteristic for the particular
chromosome, although in humans most
trisomies are lethal in early embryonic development.