Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the β-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants.

硬化性骨骼发育不良是由于骨形成和吸收之间的不平衡造成的。我们在来自四个受巨头畸形、颅骨肥厚和椎体终板硬化影响的家族的七个个体中发现了三个纯合的、C 端截短的AXIN1变异体。其他常见的发现包括髋关节发育不良、心脏畸形、不同程度的发育迟缓和血液学异常。与 AXIN1 是 β-连环蛋白破坏复合物的核心成分一致，对含有截短变体的原代细胞和基因组编辑细胞的分析揭示了基础规范 Wnt 通路活性的增强。所有三种AXIN1截短变体均导致蛋白质水平降低并损害由其 C 端 DIX 结构域介导的 AXIN1 聚合，但在过表达时部分保留了 Wnt 抑制功能。添加端锚聚合酶抑制剂可减弱AXIN1突变模型系统中的 Wnt 过度活性。我们的数据表明 AXIN1 协调成骨细胞和破骨细胞的作用，坦科聚合酶抑制剂可以减弱 AXIN1 亚形变体的作用。