Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Dis Model Mech. 2013 Sep;6(5):1227-35. doi: 10.1242/dmm.012765. Epub 2013 Jun 20.
Generalized arterial calcification of infancy (GACI), an autosomal recessive disorder, is characterized by early mineralization of blood vessels, often diagnosed by prenatal ultrasound and usually resulting in demise during the first year of life. It is caused in most cases by mutations in the ENPP1 gene, encoding an enzyme that hydrolyzes ATP to AMP and inorganic pyrophosphate, the latter being a powerful anti-mineralization factor. Recently, a novel mouse phenotype was recognized as a result of ENU mutagenesis - those mice developed stiffening of the joints, hence the mutant mouse was named 'ages with stiffened joints' (asj). These mice harbor a missense mutation, p.V246D, in the Enpp1 gene. Here we demonstrate that the mutant ENPP1 protein is largely absent in the liver of asj mice, and the lack of enzymatic activity results in reduced inorganic pyrophosphate (PPi) levels in the plasma, accompanied by extensive mineralization of a number of tissues, including arterial blood vessels. The progress of mineralization is highly dependent on the mineral composition of the diet, with significant shortening of the lifespan on a diet enriched in phosphorus and low in magnesium. These results suggest that the asj mouse can serve as an animal model for GACI.
婴儿全身性动脉钙化症（GACI）是一种常染色体隐性遗传病，其特征为血管早期矿化，通常通过产前超声诊断，且多在生命的第一年死亡。该病主要由编码一种酶的基因（ENPP1）的突变引起，该酶能将 ATP 水解为 AMP 和无机焦磷酸盐，后者是一种强大的抗矿化因子。最近，由于 ENU 诱变，一种新型的小鼠表型被识别出来，即那些关节僵硬的小鼠，因此该突变小鼠被命名为“关节僵硬的小鼠”（asj）。这些小鼠的 Enpp1 基因存在 p.V246D 错义突变。我们的研究表明，突变的 ENPP1 蛋白在 asj 小鼠的肝脏中大量缺失，且缺乏酶活性导致血浆中无机焦磷酸盐（PPi）水平降低，同时伴有包括动脉血管在内的多种组织的广泛矿化。矿化的进展高度依赖于饮食中的矿物质组成，在富含磷和低镁的饮食中，小鼠的寿命显著缩短。这些结果表明，asj 小鼠可作为 GACI 的动物模型。
