Documentation of maternal uniparental disomy of chromosome 7 in 10% of pati
ents with Russell-Silver syndrome (RSS), characterized by prenatal and post
natal growth retardation and dysmorphic features, has suggested the presenc
e of an imprinted gene on chromosome 7 whose mutation is responsible for th
e RSS phenotype, Human GRB10 on chromosome 7, a homologue of the mouse impr
inted gene Grb10, is a candidate, because GRB10 has a suppressive effect on
growth, through its interaction with either the IGF-I receptor or the GH r
eceptor, and two patients with RSS were shown to have a maternally derived
duplication of 7p11-p13, encompassing GRB10. In the present study, we first
demonstrated that the GRB10 gene is also monoallelically expressed in huma
n fetal brain tissues and is transcribed from the maternally derived allele
in somatic-cell hybrids. Hence, human GRB10 is imprinted. A mutation analy
sis of GRB10 in 58 unrelated patients with RSS identified, within the N-ter
minal domain of the protein, a P95S substitution in two patients with RSS.
In these two cases, the mutant allele was inherited from the mother. The fa
ct that monoallelic GRB10 expression was observed from the maternal allele
in this study suggests but does not prove that these maternally transmitted
mutant alleles contribute to the RSS phenotype.