Control of Bone Formation in Craniometaphyseal Dysplasia

描述（由申请人提供）：颅后骺端发育不良（CMD）是一种罕见的颅管状骨疾病，其特征为颅面骨中的终生矿化和骨沉积，而长骨干骺端中的骨沉积减少和张开。 最近，我们发现了跨膜蛋白ANK的突变，这是负责常染色体显性形式的CMD。ANK可能参与焦磷酸盐转运，小鼠中ANK蛋白的缺失导致进行性关节强直伴软骨钙化增加。然而，ANK的分子特性，它与其他蛋白质的相互作用，以及它的作用模式是未知的。CMD患者ANK基因突变的聚集和由突变ANK蛋白引起的骨基质表型表明CMD不仅仅是由焦磷酸转运的定量效应引起的，而是由更复杂的机制引起的。该提案的目标是提供工具并进行实验，最终发现1）ANK在骨稳态中的作用和2）突变ANK导致CMD表型的机制。

DESCRIPTION (provided by applicant): Craniometaphyseal dysplasia (CMD) is a rare craniotubular bone disorder, characterized by life-long mineralization and bone deposition in craniofacial bones, while decreased bone deposition and flaring is seen in the metaphyses of long bones. Recently, we discovered mutations in a transmembrane protein, ANK, which is responsible for the autosomal dominant form of CMD. ANK is likely to be involved in pyrophosphate transport and the loss of ANK protein in mice causes progressive ankylosis with increased cartilage calcification. However, ANK's molecular properties, its interaction with other proteins, and its mode of action are unknown. The clustering of the mutations in the ANK gene of CMD patients and the bone matrix phenotype caused by mutant ANK protein suggests that CMD is not solely caused by a quantitative effect of pyrophosphate transport, but by a more complex mechanism. The goal of this proposal is to provide tools and to perform experiments that will eventually lead to the discovery of 1) the role of ANK in bone homeostasis and 2) the mechanism of mutant ANK causing the CMD phenotype.