Mulibrey Nanism is an autosomal recessive growth disorder that affects several tissues of mesodermal origin. Severe growth failure of prenatal onset, constrictive pericardium with consequent hepatomegaly, hypoplasia of several endocrine glands with consequent hormonal deficiency, fibrosis of different organs, hydrocephaloid skull, and susceptibility to develop ovarian and Wilm's tumors characterize Mulibrey Nanism. A substantial portion of affected fetuses may be lost by early abortion, and infantile death is common. Mutations in the TRIM37 gene on chromosome 17q22-23 have been recently reported as the cause of this developmental syndrome. The investigator recently identified TRIM37 as a new TRAF domain encompassing protein. TRIM37 encodes a 964 amino acid residue protein and contains a tripartite domain (TRIM) in its N-terminus, an internal TRAF domain, and a polyacidic region with two nuclear localization signals at the C-terminus. Immunohistochemical analysis of human tissues indicates a tissue-restricted expression of TRIM37, and the analysis of its subcellular localization indicates that it can be found in cytosolic corpuscles and in nuclei, depending on the cell type. Preliminary studies on TRIM37 function indicate that it specifically interacts with Nmi and IFP35, two Myc- and STAT-binding proteins. Indeed FGF-dependent proliferative responses are compromised in Mulibrey Nanism cells, and over-expression of TRIM37 mutants inhibits c-Myc and NF-(B mediated transcription. Furthermore, a pilot analysis of the differences in gene expression profiles of skin fibroblasts from three different Mulibrey Nanism patients compared to those of normal fibroblasts indicate that Mulibrey Nanism cells express high levels of connective tissue growth factor (CTGF), a cytokine implicated in fibrogenesis. With this application, the investigators will seek to address the following questions about TRIM37:
Specific Aim 1, what are the differences in gene expression profiles in normal donor cells and cells from Mulibrey Nanism patients? Specific Aim 2, is there any alteration in the patterns of gene expression induced by cytokines in normal and Mulibrey Nanism fibroblasts? Specific Aim 3, what is the role of TRIM37 in regulating gene expression?
| Zapata, Juan M; Martinez-Garcia, Vanesa; Lefebvre, Sophie (2007) Phylogeny of the TRAF/MATH domain. Adv Exp Med Biol 597:1-24 |
| Zapata, Juan M; Lefebvre, Sophie; Reed, John C (2007) Targeting TRAfs for therapeutic intervention. Adv Exp Med Biol 597:188-201 |
