IDENTIFICATION OF NOVEL PHOSPHATE REGULATORS

描述(由申请人提供)：尽管它被证明具有广泛的重要性，但对磷酸盐稳态的调节仍然不完全清楚。除了编码不同的钠-磷共转运体的cDNA外，迄今已知的所有参与调节磷酸盐稳态的分子都是通过定义人类和小鼠不同遗传性疾病的分子基础来鉴定的，这些遗传性疾病的特征是磷酸盐稳态的异常调节。不同研究小组的这些研究已经确定了关键调控因子，包括1)PHEX，它在X连锁低磷血症(XLH)中发生突变；2)FGF23，其功能获得突变在常染色体显性遗传性低磷血症(ADHR)中被发现，以及功能丧失突变，在家族性肿瘤钙质沉着症(FTC-2)中被发现；以及3)GALNT3，一种在O-连锁糖基化启动中起重要作用的酶，其功能丧失突变被发现在另一种家族性肿瘤钙质沉着症(FTC-1)中。使用我们实验室开发的检测方法，FGF23或GALNT3功能突变的丧失被证明与血清C末端FGF23浓度的急剧增加有关，但FGF23水平正常。这些发现表明，FGF23需要翻译后修饰才能进行正常的细胞内加工，并可能通过一些已知的可能招募Klotho作为辅助受体的成纤维细胞生长因子受体来介导其作用。利用定位克隆策略，我们最近确定了Napi-LLC突变是遗传性低磷性软骨病伴高钙尿症(HHRH)的原因，从而为Napi-LLC在肾脏磷酸盐转运中发挥重要作用的结论提供了第一个证据。然而，尽管在识别磷酸盐稳态的关键调节因子方面取得了这些进展，但在很大程度上仍然不确定所识别的蛋白质如何以及在多大程度上有助于调节磷酸盐稳态，并且很可能有更多的蛋白质参与这些调控机制。为了进一步探索磷酸盐稳态的生物学，我们现在建议通过寻找导致常染色体隐性磷酸盐消耗障碍的分子缺陷来鉴定一种新的磷酸盐稳态调节因子，该疾病与骨硬化症相关。我们将这种疾病定位在染色体4q21上，一旦已知致病基因突变，我们将开始探索导致磷酸盐消耗和骨硬化的潜在病理生理机制。此外，我们将确定HPOS基因产物是否在健康个体的磷酸盐稳态调节中发挥作用。除了定义一种罕见的遗传性疾病外，这些努力还可能为治疗更常见的低磷和高磷疾病提供新的治疗方法，这些疾病也会影响骨代谢，例如X-连锁低磷血症(XLH)和慢性肾脏疾病(CDK)。。

DESCRIPTION (provided by applicant): Despite its demonstrated broad importance, the regulation of phosphate homeostasis remains incompletely understood. With the exception of cDNAs encoding different sodium-phosphate co-transporters, all molecules thus far known to be involved in regulating phosphate homeostasis have been identified by defining the molecular basis of different hereditary disorders in humans and mice that are characterized by an abnormal regulation of phosphate homeostasis. These studies by different groups have led to the identification of key regulators, including 1) PHEX, which is mutated in X-linked hypophosphatemia (XLH), 2) FGF23, for which gain-of-function mutations were found in autosomal dominant hypophosphatemic rickets (ADHR) and loss-of-function mutations in a form of familial tumoral calcinosis (FTC-2), and 3) GALNT3, an enzyme important for the initiation of O-linked glycosylation, for which loss-of-function mutations were identified in another familial form of tumoral calcinosis (FTC-1). Using the assay that was developed in our laboratory, loss of function mutations in either FGF23 or GALNT3 were shown to be associated with a dramatic increase in the serum concentration of C-terminal FGF23, yet normal intact FGF23 levels. These findings indicated that FGF23 requires post-translational modifications for normal intracellular processing and possibly for mediating its actions through some of the known FGF receptors that may recruit Klotho as a co-receptor. Using a positional cloning strategy, we recently identified NaPi-llc mutations as the cause of hereditary hypophosphatemic rickets with hypercalciuria (HHRH), thereby providing first evidence for the conclusion that NaPi-llc has a major role in renal phosphate handling. However, despite these advances in the identification of key regulators of phosphate homeostasis, it remains largely uncertain how and to what extent the identified proteins contribute to the regulation of phosphate homeostasis, and it is very likely that additional proteins are involved in these regulatory mechanisms. To explore the biology of phosphate homeostasis further, we now propose to identify a novel regulator of phosphate homeostasis by searching for the molecular defect leading to an autosomal recessive phosphate-wasting disorder that is associated with osteosclerosis. We mapped this disorder to chromosome 4q21, and once the disease-causing genetic mutation is known, we will begin exploring the underlying pathophysiological mechanisms leading to phosphate-wasting and osteosclerosis. Furthermore, we will determine whether the HPOS gene product has a role in the regulation of phosphate homeostasis in healthy individuals. In addition to defining a rare genetic disorder, these efforts may provide novel therapeutic approaches for the treatment of more common hypo- and hyperphosphatemic conditions that also affect bone metabolism, such as X-linked hypophosphatemia (XLH) and chronic kidney disease (CDK), respectively. .