Biallelic ENPP1 deficiency in humans induces generalized arterial calcification of infancy (GACI) and/or autosomal recessive hypophosphatemic rickets type 2 (ARHR2). The latter is characterized by markedly increased circulating FGF23 levels and renal phosphate wasting, but aberrant skeletal manifestations associated with heterozygous ENPP1 deficiency are unknown. Here, we report three adult men with early onset osteoporosis who presented with fractures in the thoracic spine and/or left radius, mildly elevated circulating FGF23, and hypophosphatemia. Total hip bone mineral density scans demonstrated osteoporosis (Z-score < -2.5) and HRpQCT demonstrated microarchitectural defects in trabecular and cortical bone. Next-generation sequencing revealed heterozygous loss-of-function mutations in ENPP1 previously observed as biallelic mutations in infants with GACI. In addition, we present bone mass and structure data as well as plasma pyrophosphate (PPi) data of two siblings suffering from ARHR2 in comparison to their heterozygous and wild-type family members indicative of an ENPP1 gene dose effect. The skeletal phenotype in murine Enpp1 deficiency yielded nearly identical findings. Ten-week-old male Enpp1 asj/asj mice exhibited mild elevations in plasma FGF23 and hypophosphatemia, and micro-CT analysis revealed microarchitectural defects in trabecular and cortical bone of similar magnitude to HRpQCT defects observed in humans. Histomorphometry revealed mild osteomalacia and osteopenia at both 10 and 23 weeks. The biomechanical relevance of these findings was demonstrated by increased bone fragility and ductility in Enpp1 asj/asj mice. In summary, ENPP1 exerts a gene dose effect such that humans with heterozygous ENPP1 deficiency exhibit intermediate levels of plasma analytes associated with bone mineralization disturbance resulting in early onset osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

中文翻译：

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人类杂合子 ENPP1 缺乏症与早发性骨质疏松症有关，这是一种在 Enpp1 缺乏症小鼠模型中概括的表型。

人类双等位基因 ENPP1 缺乏会导致婴儿全身动脉钙化 (GACI) 和/或常染色体隐性遗传性低磷性佝偻病 2 型 (ARHR2)。后者的特征是循环 FGF23 水平显着增加和肾磷酸盐消耗，但与杂合 ENPP1 缺乏相关的异常骨骼表现尚不清楚。在这里，我们报告了三名患有早发性骨质疏松症的成年男性，他们出现胸椎和/或左桡骨骨折、循环 FGF23 轻度升高和低磷血症。全髋骨矿物质密度扫描显示骨质疏松症（Z 评分 < -2.5），HRpQCT 显示小梁骨和皮质骨的微结构缺陷。下一代测序揭示了 ENPP1 中的杂合功能丧失突变，以前在 GACI 婴儿中观察到双等位基因突变。此外，我们提供了两个患有 ARHR2 的兄弟姐妹的骨量和结构数据以及血浆焦磷酸盐 (PPi) 数据，与他们的杂合子和野生型家庭成员相比，表明 ENPP1 基因剂量效应。小鼠 Enpp1 缺陷的骨骼表型产生了几乎相同的发现。10 周大的雄性 Enpp1 asj/asj 小鼠血浆 FGF23 和低磷血症轻度升高，微 CT 分析显示骨小梁和皮质骨的微结构缺陷与人类观察到的 HRpQCT 缺陷相似。组织形态测量显示在 10 周和 23 周有轻度骨软化和骨质减少。这些发现的生物力学相关性通过 Enpp1 asj/asj 小鼠的骨脆性和延展性增加得到证明。总之，ENPP1 发挥基因剂量效应，使患有杂合 ENPP1 缺陷的人表现出中等水平的血浆分析物，与骨矿化障碍相关，导致早发性骨质疏松症。© 2019 作者。美国骨与矿物质研究学会出版的骨与矿物质研究杂志。