The genetics and pathophysiology of impaired Wnt signaling in metabolic syndrome

描述（由申请人提供）：代谢综合征是糖尿病和冠状动脉疾病（CAD）发展的主要危险因素，这是世界范围内发病率和死亡率最常见的两种原因。通过对常染色体显性早发性冠状动脉疾病（CAD）、糖尿病、高脂血症、高血压和骨质疏松症大家族的遗传连锁分析，我们已经确定了导致突变的疾病，这些突变取代了低密度脂蛋白受体样蛋白（LRP6）中进化上高度保守的氨基酸，LRP6是Wnt信号通路的共同受体。进一步的研究表明，这些突变损害了Wnt信号，并影响了这些种类中存在的代谢综合征的许多组成部分。这些发现建立了LRP6突变引起的Wnt信号损伤与代谢综合征之间的因果关系，并提出了该突变的复杂下游效应的可能性，值得进一步研究。口服糖耐量试验和对LRP6突变携带者肝内脂肪含量的研究表明，LRP6突变导致糖耐量受损的根本原因是胰岛素敏感性受损。我们建立了LRP6基因敲除小鼠，在体内研究LRP6突变引起的代谢综合征的生理和细胞机制。在西方饮食的杂合子敲除小鼠中，IPGTT的初步结果表明，葡萄糖刺激胰岛素水平升高，肝糖原含量降低。骨骼肌糖原合成减少是家族性2型糖尿病患者常见的遗传性疾病。遗传性糖原合成受损的分子基础尚不清楚。GSK32是一种受Wnt信号通路反向调控的信号肽。我们的研究表明，GSK32在LRP6小鼠组织中过度表达和激活。GSK3通过磷酸化丝氨酸/酪氨酸残基抑制糖原合成酶活性。我们的目的是研究LRP6突变对LRP6小鼠糖原合成酶活性和糖原合成的影响，并在该模型中确定胰岛素抵抗的原发位点。此外，对LRP6突变携带者的临床研究表明，该突变可能导致β细胞缺陷。在单独的研究中，我们将检查LRP6小鼠胰岛的胰岛素分泌能力。此外，我们将筛选60例家族性早期CAD、代谢综合征和骨质疏松症患者的LRP6突变，以确定LRP6突变的谱和患病率，并建立基因型-表型相关性。公共卫生相关性：冠状动脉疾病（CAD）和代谢综合征是西方世界发病率和死亡率的两个最常见原因。代谢综合征的风险因素彼此之间以及与冠状动脉疾病之间的联系仍不得而知。我们已经在几个有早期冠状动脉疾病和代谢综合征的家族中发现了致病基因。所鉴定的疾病基因（LRP6）是一种辅助受体，在正常情况下激活称为Wnt信号通路的信号通路。这种途径在携带其中一种突变的患者中受损。我们的发现首次证明了该通路的损伤与人类CAD和代谢综合征的发展之间的关系。目前的研究目标是研究我们在实验室中创造的这种突变的小鼠模型的疾病机制。此外，我们计划筛选一些具有遗传性CAD、代谢综合征和骨质疏松症的家族，寻找该基因内的突变，以识别新的突变并研究其致病机制。

DESCRIPTION (provided by applicant): Metabolic syndrome is a major risk factor for development of diabetes and coronary artery disease (CAD), two most common causes of morbidity and mortality worldwide. By genetic linkage analysis in large kindreds with autosomal dominant premature coronary artery disease (CAD), diabetes hyperlipidemia, hypertension, and osteoporosis we have identified the disease causing mutations that substitute evolutionarily highly conservative amino acids in the LDL receptor like protein (LRP6), a co-receptor in the Wnt signaling pathway. Further studies have revealed that the mutations impair the Wnt signaling and impact many component of the metabolic syndrome that is present in these kindreds. These findings have established a causal link between Wnt signaling impairment caused by LRP6 mutation and metabolic syndrome and raises the possibility of complex downstream effects of the mutation which warrant further investigation. Oral glucose tolerance tests and studies of intrahepatic fat content in LRP6 mutation carriers have indicated that the underlying cause of impaired glucose tolerance caused by LRP6 mutation is impaired insulin sensitivity. We have created a LRP6 knockout mouse to investigate physiological and cellular mechanisms of metabolic syndrome caused by LRP6 mutation in vivo. Preliminary results from IPGTT in heterozygote knockout mice on Western diet has demonstrated increased glucose stimulated insulin levels and reduced hepatic glycogen content. Reduced glycogen synthesis in the skeletal is a common heritable disorder in patients with familial type 2 diabetes. The molecular basis for inherited impaired glycogen synthesis is not well understood. GSK32 is a signal peptide that is inversely regulated by the Wnt signaling pathway. Our studies have shown that GSK32 is excessively expressed and activated in LRP6 mice tissues. GSK3 inhibits glycogen synthase activity by phosphorylation of its serine/tyrosine residues. Our goal is to study the effect of LRP6 mutation on glycogen synthase activity and glycogen synthesis in LRP6 mice and to identify the primary site of insulin resistance in this model. In additional, clinical studies in LRP6 mutation carriers suggest that the mutation may cause beta cell defect. In separate studies we will examine the insulin secretory capacity of the pancreatic islets in LRP6 mice. In addition, we will screen 60 recruited kindreds with familial early CAD, metabolic syndrome and osteoporosis for mutations in LRP6, in order to identify the spectrum and prevalence of LRP6 mutation and establish genotype-phenotype correlations. PUBLIC HEALTH RELEVANCE: Coronary artery disease (CAD) and the metabolic syndrome are two most common causes of morbidity and mortality in the Western world. What links the risk factors of the metabolic syndrome to each other and to coronary artery disease remains vastly unknown. We have identified the disease causing gene in several families with early coronary artery disease and metabolic syndrome. The identified disease gene (LRP6) is a co-receptor that in normal condition activates a signaling pathway known as Wnt signaling pathway. This pathway is impaired in patients who carry one of these mutations. Our finding is the first evidence for relationship between impairment of this pathway and development of CAD and metabolic syndrome in humans. The current study goals are to investigate the disease mechanisms in a mouse model of this mutation that we have created in the lab. Moreover, we plan to screen number of families with inherited CAD, metabolic syndrome, and osteoporosis for mutations within this gene to identify novel mutations and to investigate their disease causing mechanisms.