Duplication of 7p11.2-p13, Including GRB10, in Silver-Russell Syndrome

• Published in: American journal of human genetics 2000-01, Vol.66 (1), p.36-46
• Main Authors: Monk, David, Wakeling, Emma L, Proud, Virginia, Hitchins, Megan, Abu-Amero, Sayeda N., Stanier, Philip, Preece, Michael A., Moore, Gudrun E
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; Adolescent; Adult; Animals; Biological and medical sciences; Blotting, Southern; Cell Nucleus - metabolism; Child; Child, Preschool; Chromosome 7p11.2-p13 duplication; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 7; Diseases of the osteoarticular system; Dosage; Female; Fetal Growth Retardation - genetics; Gene Duplication; Genomic Imprinting; GRB10; GRB10 Adaptor Protein; Growth Disorders - genetics; Humans; Imprinting; In Situ Hybridization, Fluorescence; Infant; Lymphocytes - metabolism; Lymphocytes - ultrastructure; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Microsatellite Repeats; Proteins - genetics; Proteins - metabolism; Replication, asynchronous; Syndrome
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/302717

Silver-Russell syndrome (SRS) is characterized by pre- and postnatal growth failure and other dysmorphic features. The syndrome is genetically heterogenous, but maternal uniparental disomy of chromosome 7 has been demonstrated in ∼7% of cases. This suggests that at least one gene on chromosome 7 is imprinted and involved in the pathogenesis of SRS. We have identified a de novo duplication of 7p11.2-p13 in a proband with features characteristic of SRS. FISH confirmed the presence of a tandem duplication encompassing the genes for growth factor receptor–binding protein 10 ( GRB10) and insulin-like growth factor–binding proteins 1 and 3 ( IGFBP1 and - 3) but not that for epidermal growth factor–receptor ( EGFR). Microsatellite markers showed that the duplication was of maternal origin. These findings provide the first evidence that SRS may result from overexpression of a maternally expressed imprinted gene, rather than from absent expression of a paternally expressed gene. GRB10 lies within the duplicated region and is a strong candidate, since it is a known growth supressor. Futhermore, the mouse homologue ( Grb10/Meg1) is reported to be maternally expressed and maps to the imprinted region of proximal mouse chromosome 11 that demonstrates prenatal growth failure when it is maternally disomic. We have demonstrated that the GRB10 genomic interval replicates asynchronously in human lymphocytes, suggestive of imprinting. An additional 36 SRS probands were investigated for duplication of GRB10, but none were found. However, it remains possible that GRB10 and/or other genes within 7p11.2-p13 are responsible for some cases of SRS.