Patterns of gene expression in Mulibrey Nanism

描述（由申请人提供）：多发性Nanism是一种常染色体隐性生长疾病，影响几种中胚层起源的组织。产前严重生长衰竭，心包收缩导致肝肿大，几个内分泌腺发育不全导致激素缺乏，不同器官纤维化，颅骨类脑积水，易患卵巢和Wilm肿瘤。很大一部分受影响的胎儿可能因早期流产而丢失，婴儿死亡很常见。染色体17q22-23上的TRIM37基因突变最近被报道为导致这种发育综合征的原因。研究者最近发现TRIM37是一种新的包含TRAF结构域的蛋白。TRIM37编码一个964个氨基酸的残基蛋白，其n端包含一个trim3结构域（TRIM），一个内部TRAF结构域，以及一个在c端具有两个核定位信号的多酸区。人体组织免疫组化分析显示TRIM37的组织限制性表达，其亚细胞定位分析表明，根据细胞类型，它可以在细胞质小体和细胞核中发现。对TRIM37功能的初步研究表明，它与两种Myc和stat结合蛋白Nmi和IFP35特异性相互作用。事实上，在multi - Nanism细胞中，fgf依赖性的增殖反应受到损害，TRIM37突变体的过表达抑制了c-Myc和NF- B介导的转录。此外，与正常成纤维细胞相比，来自三种不同的mulbrey Nanism患者的皮肤成纤维细胞基因表达谱差异的初步分析表明，mulbrey Nanism细胞表达高水平的结缔组织生长因子（CTGF），这是一种与纤维形成有关的细胞因子。

DESCRIPTION (provided by applicant): 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?