The aim of this proposal is the generation of mouse models to study Mulibrey Nanism. The Trim37 gene on chromosome 17q22-23 was reported to be mutated in patients with Mulibrey Nanism, an autosomal recessive disorder that affects several tissues of mesodermal origin. Mulibrey Nanism is characterized by severe growth failure of prenatal onset, hypoplasia of several endocrine glands with consequent hormonal deficiency, constrictive pericardium, hepatomegaly, hydrocephaloid skull, muscle hypotonia and susceptibility to develop ovarian and Wilm's tumors. A substantial portion of affected fetuses may be lost by early abortion and infantile death is common. Current treatment is limited to pericardiectomy and routine hormone replacement. Thus, TRIM37 plays important roles in human development and tumorigenesis, but the biochemical mechanism of action of the protein remains unknown. Trim37 encodes a 964 aa protein encompassing a tripartite domain (TRIM) in its N-terminus, an internal TRAF domain, and a polyacidic C-terminal region with two nuclear localization signals. Preliminary studies of the biochemistry of this protein suggest that it might be involved in the regulation of STAT and Myc pathways. With funding of this proposal, we seek to: 1. generate a mouse lineage lacking TRIM37 expression; 2. obtain mice expressing the FINmajor mutation of TRIM37 found in patients with Mulibrey Nanism; and 3. study the developmental and phenotypic alterations of trim37 knock out and FINmajor-mutated trim37 mice. These mice will be the foundation for further studies on the biology and etiology of Mulibrey Nanism.
| 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 |
| Samuel, Temesgen; Welsh, Kate; Lober, Thomas et al. (2006) Distinct BIR domains of cIAP1 mediate binding to and ubiquitination of tumor necrosis factor receptor-associated factor 2 and second mitochondrial activator of caspases. J Biol Chem 281:1080-90 |
| Fukushima, Toru; Zapata, Juan M; Singha, Netai C et al. (2006) Critical function for SIP, a ubiquitin E3 ligase component of the beta-catenin degradation pathway, for thymocyte development and G1 checkpoint. Immunity 24:29-39 |
