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The Silver-Russell syndrome (also known as Russell-Silver syndrome [RSS]
- OMIM 180860) is clinically heterogeneous but is primarily characterized by
intrauterine and post natal growth retardation, body asymmetry, characteristic
facial features, and sexual precocity. Abnormalities of chromosomes 7, 8, 11,
15, 17, and 18 have been found in RSS patients, and maternal uniparental isodisomy
for chromosome 7 has been identified in ~10% of subjects. Chromosome 7 has
2 imprinted regions - 7p11.2-p13 and 7q31-qter. Since fetal growth disorders
have been associated with epigenetic errors in several imprinted genes located
at chromosome 11p15 (eg, Beckwith-Wiedemann syndrome[BWS]), the investigators
examined this area in 9 children with RSS. Within this region are 2 maternally
imprinted and paternally expressed genes - IGF2; KCNQ1OT1 - and 2
paternally imprinted and maternally expressed genes - H19, CDKN1C;
no pathologic mutations have been found in these genes in RSS individuals.
Five of the RSS subjects had partial loss of methylation of the H19 promoter,
of the H19-IGF2 imprinting center region-1 located upstream of H19,
and of the IGF2 differentially methylated region (DMR)-2 in exon 9.
One of the patients had an identical twin that did not have
RSS! This child also had partial loss of methylation of H19 and of
the imprinting region in leukocyte DNA but not in fibroblast DNA indicating
that she was mosaic for this trait and thus clinically unaffected implying
a quantitative effect of methylation on expression of the clinical disease.
This was further substantiated by the observation that the expression of IGF2 in
fibroblasts from the affected twin (and other RSS patients) was but a small
fraction of that in the unaffected twin=s fibroblasts and other control subjects.
The authors concluded that there was partial loss of methylation on the paternally
inherited imprinted 11p15 region that resulted in “relaxation” of
imprinting. Since expression of paternal IGF2 requires methylation
of its DMR-2 in exon 9, partial loss of methylation (as in subjects with RSS)
leads to decreased IGF2 expression and consequently pre- and postnatal
growth retardation. The investigators suggested that partial loss of paternal
methylation occurred after fertilization and resulted in a mosaic pattern of
the epimutation leading to body asymmetry, but the mechanism of this alteration
is unclear. It should also be noted that 4 RSS patients did not have an abnormality
of methylation at chromosome 11p15, emphasizing the genetic heterogeneity of
this disorder.
Gicquel C, Rossignol S, Cabrol S, et al. Epimutation of the telomeric imprinting
center region on chromosome 11p15 in Silver-Russell syndrome. Nature Genet.
2005;37:1003 - 1007.
Editor’s Comment: The RSS appears to
be due to an abnormality that is the reciprocal of that present in patients
with the BWS that is characterized by excessive in utero and postnatal growth,
organomegaly, hemihyperplasia, hypoglycemia due to hyperinsulinism, and a
predisposition to tumor formation (particularly Wilm’s tumor) and is
associated with biallelic expression of IGF2 and excessive production of
IGF-II. In ~10% of subjects with BWS there is hypermethylation of the H19
promoter and of IGF2 DMR-2 and consequently IGF2 expression from both maternal
and paternal alleles. Further studies of the regulation of IGF-II production
and function in subjects with intrauterine growth retardation not associated
with RSS would be of interest. Furthermore, IGF-II might be helpful in the
treatment of children with RSS.
Epigenetics is the “study of heritable changes in gene function
that occur without a change in the DNA sequence”.1 Epimutations
are chemical changes in DNA or histone proteins associated with DNA that
may change the structure of a gene without altering its nucleotide sequence.1,2 Epigenetic
changes lead to structural modifications in gene DNA that make it more or
less accessible to (transcription) factors that regulate gene expression.
Such changes include DNA methylation, histone deacetylation (or demethylation
or acetylation, respectively), and RNA silencing. Epigenetic changes are
heritable and often parenterally specific. Although DNA methylation often
Asilences@ gene transcription (as on the inactivated X chromosome), methylation
of IGF2 enhances its transcription. In addition to IGF2, other imprinted
genes have also been important for fetal growth including that encoding the
IGF-II receptor. The incidence of imprinting disorders such as BWS is substantially
increased in children conceived with assisted reproductive technologies.1
Allen W. Root, MD
References - (linked to  )
- Jacob S, Moley KH. Gametes and embryo epigenetic reprogramming affect developmental
outcome: Implication for assisted reproductive technologies. Pediatr Res. 2005;58:437
- 446.
- Schubeler D, Elgin SC. Defining epigenetic states through chromatin and
RNA. Nature Genet, 2005;37:917 - 918.
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Current GGH - Vol. 24 No. 1
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