Session: OR20-Genetics of Growth
Bench to Bedside
Room 122 (Moscone Center)
Primordial dwarfism (PD) describes a group of disorders that are characterised by severe pre- and postnatal growth restriction resulting in significant short stature. Over recent years genetic analysis has identified mutations in several genes as causing different PD conditions. This includes CUL7, OBSL1 and CCDC8 mutations which cause one of the most common forms of PD, 3-M syndrome. Although many genes have been identified as causing PD the molecular pathways responsible are largely unknown. 3-M syndrome is unique amongst PD conditions in that the phenotype is almost exclusively growth related with no other system disorder and thus is an ideal model to study disrupted human growth processes.
We have previously shown OBSL1 interacts with both CCDC8 and CUL7 suggesting a shared 3-M pathway exists and this study used an immunoprecipitation/mass spectrometry (IP/MS) approach to identify proteins that interact with CUL7, OBSL1 and CCDC8 in order to create a 3-M disease network model- the ‘3-M interactome’.
We identified protein-protein interaction networks comprising of 503 putative CUL7 interacting proteins, 492 putative OBSL1 interacting proteins and 521 putative CCDC8 interacting proteins with an overlap of 176 proteins that interact with all three. Reactome analysis of these 176 proteins revealed that RNA processing, ribosomal, cell cycle, DNA repair and apoptotic proteins show significant over-representation. The heterogeneous ribonucleoprotein (HNRNP) spliceosome complex shows a particularly high level of enrichment in each of the IP/MS datasets suggesting that regulation of alternative splicing via the HNRNP complex may be an important molecular mechanism in 3-M. Furthermore we identified that OBSL1 IP shows enrichment of Golgi apparatus transport complexes and CCDC8 IP with proteins involved in membrane trafficking. These observations are in keeping with the previously postulated molecular function and cellular localisation of these proteins.
Genes associated with cell cycle and DNA repair pathways have been previously associated with other PD conditions including Seckel syndrome and MOPDII. This may indicate that these pathways are central to normal human growth. Further exploration of these pathways in relation to cellular growth in PD will aid our understanding of the human growth process and possibly lead to future drug targets for therapeutic intervention adjuvant to GH/IGF-I in treating short stature.
Nothing to Disclose: DH, AS, PEC
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