Maternal UPD 7, Silver-Russell Syndrome, and Imprinted Candidate Genes
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Drs. David Monk and Gudrun Moore
The Institute of Reproductive & Developmental Biology,
Imperial College London, United Kingdom
Silver-Russell syndrome (SRS) is characterised by pre- and postnatal growth restriction and additional dysmorphic features including body asymmetry and fifth finger clindactyly. The syndrome is genetically heterogeneous, with a number of chromosomes implicated. However, maternal UPD for chromosome 7 (mUPD7) has been demonstrated in up to 10 percent of cases. This observation suggests that altered imprinted gene expression is involved in the pathogenesis of the syndrome. Overexpression of a maternally transcribed, imprinted gene with growth suppressing activity, or the lack of paternally imprinted gene expression could account for the phenotype.
Recent molecular mapping of SRS patients with subtle chromosome 7 disruptions has revealed two candidate gene regions, both of which harbour imprinted genes. The 7p11.2-p13 region is defined by three unrelated SRS patients with maternally inherited duplications. This region contains the solitary imprinted gene GRB10.
A single SRS patient with segmental mUPD 7q32-qter defines the second candidate region. Within this interval maps the MEST, MESTIT1, 2- COP, and CPA4 imprinted genes. No coding or epigenetic mutations for any imprinted gene have been found in SRS patients to date. It is therefore believed that additional imprinted genes must map to these locations. Strategies for the isolation of novel imprinted genes in the mouse orthologous imprinted regions will also be discussed.