Nagle D L, McGrail S H, Vitale J, Woolf E A, Dussault B J, DiRocco L, Holmgren L, Montagno J, Bork P, Huszar D, Fairchild-Huntress V, Ge P, Keilty J, Ebeling C, Baldini L, Gilchrist J, Burn P, Carlson G A, Moore K J
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Nature. 1999 Mar 11;398(6723):148-52. doi: 10.1038/18210.
Genetic studies have shown that mutations within the mahogany locus suppress the pleiotropic phenotypes, including obesity, of the agouti-lethal-yellow mutant. Here we identify the mahogany gene and its product; this study, to our knowledge, represents the first positional cloning of a suppressor gene in the mouse. Expression of the mahogany gene is broad; however, in situ hybridization analysis emphasizes the importance of its expression in the ventromedial hypothalamic nucleus, a region that is intimately involved in the regulation of body weight and feeding. We present new genetic studies that indicate that the mahogany locus does not suppress the obese phenotype of the melanocortin-4-receptor null allele or those of the monogenic obese models (Lep(db), tub and Cpe(fat)). However, mahogany can suppress diet-induced obesity, the mechanism of which is likely to have implications for therapeutic intervention in common human obesity. The amino-acid sequence of the mahogany protein suggests that it is a large, single-transmembrane-domain receptor-like molecule, with a short cytoplasmic tail containing a site that is conserved between Caenorhabditis elegans and mammals. We propose two potential, alternative modes of action for mahogany: one draws parallels with the mechanism of action of low-affinity proteoglycan receptors such as fibroblast growth factor and transforming growth factor-beta, and the other suggests that mahogany itself is a signalling receptor.
遗传学研究表明，桃花心木基因座内的突变可抑制刺豚鼠致死黄色突变体的多效性表型，包括肥胖。在此，我们鉴定了桃花心木基因及其产物；据我们所知，这项研究代表了小鼠中首个抑制基因的定位克隆。桃花心木基因的表达广泛；然而，原位杂交分析强调了其在下丘脑腹内侧核表达的重要性，该区域与体重和进食调节密切相关。我们开展了新的遗传学研究，结果表明桃花心木基因座不会抑制黑皮质素-4-受体无效等位基因或单基因肥胖模型（Lep(db)、tub和Cpe(fat)）的肥胖表型。然而，桃花心木基因可抑制饮食诱导的肥胖，其机制可能对常见人类肥胖的治疗干预具有启示意义。桃花心木蛋白的氨基酸序列表明，它是一个大型的、具有单个跨膜结构域的类受体分子，其短细胞质尾巴含有一个在秀丽隐杆线虫和哺乳动物之间保守的位点。我们提出了桃花心木基因两种潜在的、可供选择的作用模式：一种与低亲和力蛋白聚糖受体（如成纤维细胞生长因子和转化生长因子-β）的作用机制相似，另一种表明桃花心木基因本身就是一种信号受体。
