Abnormal Epigenetic Regulation in Mendelian Disorders and Uniparental Disomy 181

(A) TRISOMY RESCUE (B) MONOSOMY RESCUE

Figure 6.21 Uniparental disomy can
arise by post-zygotic trisomy rescue or
monosomy rescue. (A) Shown in the center is
disomy 11 nullisomy 11 one type of trisomic zygote (with two maternal
egg egg homologs plus one paternal chromosome, in this
case chromosome 11). Trisomy 11 is lethal, but
the trisomy can be corrected in the very early
embryo by the loss of a chromosome 11 from one
embryonic cell that then has a growth advantage
and goes on ultimately to form an individual
trisomy 11 monosomy 11 with the correct number of chromosomes. The
zygote zygote
disomic cell (and individual) may be normal (one
paternal 11 plus one maternal 11) or have the two
alternatives for loss of one maternal chromosome 11 homologs (uniparental
homolog in very early embryo duplication heterodisomy). (B) Monosomy rescue can occur by
chromosome duplication, but in this case the result
is uniparental isodisomy (the two chromosomes are
identical, not homologs).

normal normal maternal paternal

heterodisomy 11 isodisomy 11

Genetics in Medicine | A0621

Tom Strachan |
mother.
© It occurs
garland science most
studio often
after a trisomic conceptus is first formed
design by blink limited
with two chromosome homologs from one parent and a single chro-
mosome copy from the other parent; loss of the latter chromosome
very early in development results in a heterodisomy (Figure 6.21A). The
alternative is monosomy rescue, which results in isodisomy (with two
identical copies of a chromosome—see Figure 6.21B). As described in the
next section, uniparental disomy can result in a disorder of development
if the chromosome happens to contain imprinted genes that are impor-
tant in development.

Abnormal gene regulation at imprinted loci

At an imprinted locus only one of the two parental alleles is consistently
expressed (in at least some tissues), and alteration of the normal pattern
of monoallelic expression can result in disease. Certain imprinted genes
are important in fetal growth and development, so in these cases abnor-
mal expression often results in recognizable developmental syndromes.
Sometimes the normally expressed allele is not present or is defective,
and deficiency of a gene product causes disease. In other cases, disease
can be due to overexpression of a dosage-sensitive gene (Table 6.7).
Analysis of human imprinting disorders has helped us understand the
underlying gene regulation. For example, a cluster of at least 10 imprinted
genes in the subtelomeric 11p15.5 region has been well studied because
of associations with Beckwith–Wiedeman syndrome (PMID 20301499)
and many cases of Silver–Russell syndrome (PMID 20301568). The gene
cluster has two different imprinting control regions, ICR1 and ICR2.
Figure 6.22A shows some key 11p15.5 genes regulated by ICR1 and ICR2.
Both ICR1 and two nearby enhancer elements regulate IGF2 (insulin
growth factor type 2; paternally expressed) and H19 (which makes a
maternally expressed ncRNA). ICR2 regulates the KCNQ1 gene (which
makes a maternally expressed potassium channel), the KCNQ1OT1 anti-
sense RNA transcript (KCNQ1 opposite strand transcript 1; paternally
expressed), and CDKN1C (a suppressor of cell proliferation; maternally
expressed).
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