Functional analysis of a novel metabolic syndrome related gene

肥胖相关基因3，即肌小管蛋白相关蛋白9 （MTMR9）基因的snp与肥胖和高血压有关。37UTR中存在SNPs危险等位基因的mRNA比不存在危险等位基因的mRNA更不稳定，这表明肥胖患者MTMR9的mRNA水平会降低。在鼠类下丘脑外侧区和弓形核中均检测到MTMR9的转录本和蛋白，该蛋白与浓缩激素、神经肽Y （NPY）和促黑素原共存。MTMR9属于肌球蛋白家族，具有蛋白酪氨酸磷酸酶活性。然而，MTMR9缺乏磷酸酶活性。MTMR9与活性磷酸酶MTMR6和MTMR7相互作用。MTMR9和MTMR7蛋白在同一细胞中表达，提示MTMR9可能与MTMR7一起作用于下丘脑区。小鼠下丘脑区MTMR9转录物水平在禁食后升高，高脂饮食与NPY和AGRP同时降低。因此，MTMR9可能参与食欲调节。MTMR9转录物水平在ob/ob或db/db小鼠与对照小鼠之间没有差异。这些数据提示MTMR9可能是瘦素信号的下游。我们在一项大规模病例对照关联研究中确定了可能影响肥胖和高血压风险的MTMR9基因变异。我们已经证明了MTMR9参与食欲调节的可能性。

SNPs in the obesity-related gene 3, that is myotubularin-related protein 9 (MTMR9) gene, was associated with obesity and hypertension. The mRNA with risk alleles of SNPs existed in 37UTR was less stable that that without risk alleles, suggesting that the mRNA levels of MTMR9 would be reduced in obese patients. Both the transcript and protein of MTMR9 were detected in the rodent lateral hypothalamic area as well as in the arcuate nucleus, an the protein co-existed with orexin, meanin concentrating hormone, neuropeptide Y (NPY) and proopiomelanocrotin. MTMR9 is belongs to myotularin family that possesses protein-tyrosine phosphatase activities. MTMR9, however, lacks phosphatase activity. MTMR9 interacts active phosphatase MTMR6 and MTMR7. MTMR9 and MTMR7 proteins were expressed in the same cell, suggesting that MTMR9 could act in the haypothalamic region together with MTMR7. The levels of MTMR9 transcript in the murine hypothalamic region increased after fasting and were decreased by a high-fat-diet in parallel with NPY and agouti-relate protein (AGRP). Thus, MTMR9 would be involved in appetite regulation. The level of MTMR9 transcript did not differ between ob/ob or db/db and control mice. These data suggested that MTMR9 may be the downstream of lepin signal. We identified the gentic variations in MTMR9 tha may influence the risk of obesity and hypertension in a large-scale case-control association study. We have demonstrated that the possibility that MTMR9 could involved in appetite regulation.