Maternal repression of the human GRB10 gene in the developing central nervous system; evaluation of the role for GRB70 in Silver-Russell syndrome

The GRB10 gene encodes a growth suppressor and maps to human chromosome 7p1 1.2-p13. Maternal duplication (matdup) of this region has recently been ass ociated with Silver-Russell syndrome (SRS), which is characterised by pre- and postnatal growth restriction, craniofacial dysmorphism and lateral asym metry. Maternal uniparental disomy for chromosome 7 (mUPD7) occurs in appro ximately 7% of SRS patients. Exposure of a recessive allele due to isodisom y has been ruled out in five mUPD7 cases, suggesting genomic imprinting as the basis for disease. Assuming SRS patients with matdup of 7p11.2-p13 and mUPD7 share a common aetiology, this would implicate a maternally expressed gene from this interval, which is involved in growth inhibition. Murine Gr b10 was identified as a maternally expressed gene by subtractive hybridisat ion using normal and androgenetic mouse embryos. Grb10 maps to the homologo us region of proximal mouse chromosome 11, for which mUPD incurs reduced bi rthweight. A role for GRB10 in SRS was evaluated by determining its imprint ing status in multiple human foetal tissues using expressed polymorphisms, and by screening the coding region for mutations in 18 classic non-mUPD7 SR S patients. Maternal repression of GRB10 was observed specifically in the d eveloping central nervous system including brain and spinal cord, with bial lelic expression in peripheral tissues. This is in contrast to mouse Grb10, and represents the first example of opposite imprinting in human and mouse homologues. While a role for GRB10 in mUPD7 SRS cases can not be ruled out on the basis of imprinting status, no mutations were identified in the pat ients screened.