Characterisation of the growth regulating gene IMP3, a candidate for Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is characterised by preand postnatal growth restriction in association with other clinically recognised dysmorphic features such as triangular facies, asymmetry, and fifth finger clinodactyly. Since the major diagnostic features involve reduced growth, it is tempting to postulate that altered expression of a protein within a growth factor cascade may be causative. There have been numerous documented defects of genes coding for proteins in the insulin-like growth factor (IGF) signalling pathways, whether the receptors, ligands, or signal modulators, which result in a SRS-like phenotype. Probands with ring chromosomes or deletions involving the 15q26-qter region present with growth failure and SRS-like features. It has been proposed that the phenotypes are the result of hemizygosity at the IGF1 receptor (IGF1R) gene. We have shown, however, that hemizygosity at this locus is not a common cause of SRS. 11 In addition, it has been well documented that maternal uniparental disomy (UPD) of chromosome 7 is present in approximately 10% of SRS cases and no consistent regions of isodisomy have been shown for the full length of the chromosome. This suggests that there are imprinted genes on chromosome 7, which when disrupted are responsible for the phenotype. Recently two independently reported candidate gene regions on chromosome 7 containing imprinted genes defined by cytogenetic disruptions in SRS probands have been reported. Two unrelated probands with maternally transmitted duplications of 7p11.2-p13 define the first region. 18 Recently, a number of other cytogenetic disruptions including balanced translocations and inversions within this region have been described in association with the SRS or SRS-like phenotype (Monk et al, manuscript submitted). This candidate gene region contains the growth related genes insulin-like growth factor binding proteins 1 and 3 (IGFBPs) and growth factor binding protein 10 (GRB10). The latter has been shown to be imprinted, and it is conceivable that overexpression of this gene could give rise to the phenotype in these cases. However, all of the above genes are excluded from playing a major role in the aetiology through both imprinting and mutation analyses. 20–25 The second SRS candidate region is defined by a single SRS case that resulted from segmental uniparental isodisomy for 7q32-qter. This second region is known to contain two imprinted genes, MEST and CoPg2. The human 7p11.2-p13 region is orthologous to the imprinted region on mouse proximal chromosome 11. Mice with maternal duplication of the region proximal to the T41Ad reciprocal translocations breakpoint (MatDp(prox11)) present with prenatal growth failure, a situation similar to the observed growth restriction in the duplication and mUPD(7) SRS cases. In addition to the mouse chromosome 11 imprinted region, human chromosome 7 has homology with multiple mouse chromosomal regions displaying imprinted phenotypes. Mouse proximal chromosome 6 harbours two imprinted regions and has homology with human 7q32-qter, 7q21, and 7p15. Mice with maternal duplications of chromosome 6 proximal to the T(4;6)77H reciprocal translocation breakpoint in 6A3.2 (MatDp(prox6)) define a domain that is responsible for early embryonic lethality, whereas the region between the T77H and T(6;13)6Ad breakpoints is associated with growth retardation when maternally duplicated. This second region contains the imprinted gene cluster of Mest, Copg2, Copg2AS, Mit1/Lb9 (fig 1). In this report, we describe the mapping, expression analysis, and imprinting status for the novel functional candidate gene IGF2 mRNA binding protein 3 (IMP3). IMP3 is an interesting candidate for SRS since it maps to human chromosome 7, mouse chromosome 6, and is involved with IGF2 regulation of prenatal growth. IMP3 is a member of a closely related mRNA binding protein family with a molecular mass of 64 kDa, with an overall sequence identity of 59% with other family members. IMP3 sequence is identical to the Koc (KH domain containing protein overexpressed in cancer) protein sequence derived from a pancreatic tumour cDNA screen and is thought to have an important role in the differentiation process during early human embryogenesis. The IMP proteins contain two functional RNA recognition motifs (RRM) and four hnRNP K homology domains which suggests an involvement with RNA stability or transcriptional regulation. Members of the IMP protein family have been shown to have multiple attachment sites within the 5′ UTR of IGF2 leader 3 mRNA and the 3′ UTR of H19 mRNA. H19 is a maternally expressed gene that is physically linked to the paternally expressed IGF2 gene. H19 RNA is not translated but is thought to be involved in IGF2 regulation since their imprinted expression is mechanistically linked. This link makes up the basis for the enhancer competition theory for the 11p15.5 imprinting cluster, disruptions of which are responsible for a proportion of the overgrowth phenotype seen in Beckwith-Wiedemann syndrome (BWS). It is speculated that the IMP family of proteins act as factors that are involved in the mechanical coupling of IGF2/H19 post-translational regulation. IMP1 has been shown to be involved in such a regulation, via interactions with the 6 Kb IGF2 leader 3 mRNA, but not the constitutively translated 4.8 If you have a burning desire to respond to a paper published in Journalof Medical Genetics, why not make use of our “rapid response” option? Log on to our website (www.jmedgenet.com), find the paper that interests you, and send your response via email by clicking on the “eLetters” option in the box at the top right hand corner. Providing it isn’t libellous or obscene, it will be posted within seven days. You can retrieve it by clicking on “read eLetters” on our homepage. The editors will decide as before whether to publish it in a future paper issue as well. 575