Investigation of the GRB2, GRB7, and CSH1 genes as candidates for the Silver-Russell syndrome (SRS) on chromosome 17q.

Silver-Russell syndrome (SRS) (MIM 180860) is characterised by intrauterine and postnatal growth restriction, in association with dysmorphic features most frequently including a small triangular facies, skeletal asymmetry, and fifth finger clinodactyly. The genetic aetiology of SRS is heterogeneous. Maternal uniparental disomy for chromosome 7 (mUPD(7)) occurs in 7-10% of patients, 5 with strong evidence that disruption of imprinted gene expression, as opposed to mutation of a recessive gene, underlies the SRS phenotype in these cases. A SRS-like phenotype has also been associated with ring chromosome 15 with accompanying deletion on 15q, 8 trisomy 18 mosaicism, deletion on 18p, and deletion of 8q11-q13. Three SRS cases have been described with disruptions involving distal 17q. These include two unrelated patients with severe SRS bearing reciprocal translocations, with the breakpoints originally assigned to 17q25. In the first case, the proband had an apparently balanced translocation (17;20)(q25;q13), inherited from her clinically normal father. The second patient had a de novo translocation (1;17)(q31;q25). The breakpoint in this latter case has recently been cloned and more accurately localised to 17q23.3-q24. In the third case, a heterozygous deletion of the chorionic somatomammotrophin hormone 1 (CSH1) gene, which is located within the growth hormone and CSH gene cluster on 17q24.1, was identified in a patient with typical SRS. The deletion was inherited from the father, who appeared clinically normal, but had short stature. CSH1, otherwise known as placental lactogen, is produced in the syncytiotrophoblast of the placenta and secreted into the maternal and fetal circulation. CSH1 is detectable in maternal serum from 6 weeks post conception, and levels increase linearly during gestation, peaking at about 30 weeks. CSH1 has been used as a marker for placental integrity during pregnancy, and low levels in the maternal serum have been associated with pathological conditions including intrauterine growth restriction (IUGR). CSH1 may play a role in regulation of fetal growth and metabolism by stimulating insulin-like growth factor 1 (IGF-1) production by the fetus. 17 Interestingly, the growth factor receptor binding protein (GRB) 2 and 7 genes map to 17q24-25 and 17q21-22, respectively, near the translocation breakpoints. The GRB protein family, including GRB2, GRB7, GRB10, and GRB14, function in mitogenic signalling and are likely to be important in fetal growth. Each member contains a carboxy-terminal Src homology 2 (SH2) domain. GRBs 7, 10, and 14 are structurally very similar, with an additional pleckstrin homology (PH) domain. The GRB proteins are important components of the insulin and IGF signal transduction pathways, interacting with various receptor tyrosine kinases and other tyrosine phosphorylated proteins via the SH2 domain. GRB10 has been implicated in SRS with the reports of two SRS patients with maternally inherited duplications of 7p11.2-p13 encompassing this gene. 23 GRB10 is imprinted, showing paternal expression in human fetal brain 25 and a maternally transcribed isoform has been identified in skeletal muscle. Although no sequence mutations of GRB10 have been identified in 139 SRS patients, GRB10 remains a candidate for this disorder through disruption of imprinted expression. GRB2, in association with the guanine nucleotide exchange factor, Sos, interacts with the insulin receptor substrate 1, thus regulating Ras activation. GRB2 therefore plays a significant role in the regulation of the insulin signal transduction system. GRB7 binds the Ret receptor, the epidermal growth factor receptor, and the insulin receptor. Upregulation of both GRB2 and GRB7 has been implicated in cancer metastasis. 33 One or more SRS genes must exist on distal chromosome 17q, most likely in the region 17q23-25. We investigated our cohort of SRS patients for genetic abnormalities involving the long arm of chromosome 17. Specifically, we focused on the three functional candidate genes, CSH1, GRB2, and GRB7, which map within or near the same chromosomal interval as the previous genetic defects on distal 17q associated with SRS.