A neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder.
A neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder.
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DOI：
10.1038/s41467-022-28318-4
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发表时间：
2022-02-04
影响因子：
16.6
通讯作者：
Baron J
中科院分区：
文献类型：
--
作者：
Lui JC;Raimann A;Hojo H;Dong L;Roschger P;Kikani B;Wintergerst U;Fratzl-Zelman N;Jee YH;Haeusler G;Baron J
SP 7/Osterix是成骨细胞成熟和骨形成的关键转录因子。SP 7的纯合功能丧失突变导致骨生成突变型XII，但SP 7的新形态（获得新功能）突变尚未在人类中报道。在这里，我们描述了一个从头占主导地位的neomorphic错义变异（c.926 C > G：p.S309W）在SP 7的患者颅缝早闭，颅骨肥厚，长骨脆性。组织形态计量学显示成骨细胞增加，但骨矿化减少。具有相应变体的小鼠也显示出与Sp 7缺失小鼠不同的复杂骨骼表型。该突变改变了SP 7的结合特异性，从AT丰富的基序到GC共有序列（其他SP家族成员的典型序列），并产生异常的基因表达谱，包括Col 1a 1和内源性Sp 7的表达增加，但参与基质矿化的基因表达减少。我们的研究确定了一种致病机制，其中转录因子的突变改变了DNA结合特异性，并提供了重要的体内证据，表明SP 7对富含AT的基序的亲和力，在SP蛋白中是独一无二的，对正常的成骨细胞分化至关重要。SP 7是成骨细胞分化和骨形成所需的转录因子。SP 7中的一个新变体突变被发现改变DNA结合特异性，导致小鼠和人类复杂的骨骼疾病。
SP7/Osterix is a transcription factor critical for osteoblast maturation and bone formation. Homozygous loss-of-function mutations in SP7 cause osteogenesis imperfecta type XII, but neomorphic (gain-of-new-function) mutations of SP7 have not been reported in humans. Here we describe a de novo dominant neomorphic missense variant (c.926 C > G:p.S309W) in SP7 in a patient with craniosynostosis, cranial hyperostosis, and long bone fragility. Histomorphometry shows increased osteoblasts but decreased bone mineralization. Mice with the corresponding variant also show a complex skeletal phenotype distinct from that of Sp7-null mice. The mutation alters the binding specificity of SP7 from AT-rich motifs to a GC-consensus sequence (typical of other SP family members) and produces an aberrant gene expression profile, including increased expression of Col1a1 and endogenous Sp7, but decreased expression of genes involved in matrix mineralization. Our study identifies a pathogenic mechanism in which a mutation in a transcription factor shifts DNA binding specificity and provides important in vivo evidence that the affinity of SP7 for AT-rich motifs, unique among SP proteins, is critical for normal osteoblast differentiation. SP7 is a transcription factor required for osteoblast differentiation and bone formation. A neomorphic mutation in SP7 was found to alter DNA binding specificity, causing a complex skeletal disorder in both mice and humans.
成骨细胞特异性转录因子OSX对DKK1基因调节的表征。
DOI：
10.1016/j.bbrc.2012.03.073
发表时间：
2012-04-20
影响因子：
3.1
作者：
Zhang C;Dai H;de Crombrugghe B
通讯作者：
de Crombrugghe B