Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.
N Engl J Med. 2013 May 9;368(19):1809-16. doi: 10.1056/NEJMoa1215458.
This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T→G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C→A, p.Ser295*. In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.
本报告确定了与 WNT1 突变相关的人类骨骼疾病。在 10 名具有显性遗传、早发性骨质疏松症的家族成员中，我们鉴定出 WNT1 中的杂合错义突变 c.652T→G（p.Cys218Gly）。在另一个受影响的 2 名同胞的家族中，我们鉴定出纯合无义突变 c.884C→A，p.Ser295*。体外，WNT1 蛋白的异常形式显示出诱导经典 WNT 信号、其靶基因和矿化的能力受损。在小鼠中，Wnt1 明显在骨髓中表达，特别是在 B 细胞谱系和造血祖细胞中；谱系追踪鉴定出该基因在一部分成骨细胞中的表达，表明在这些疾病中，造血和成骨谱系细胞之间的 WNT 信号存在异常的串扰。
