PDF(Pubmed)
Abstract：
Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our previous studies have shown that gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2) are responsible for cherubism and that a knock-in mouse model for cherubism recapitulates the features of cherubism, such as increased osteoclast formation and jawbone destruction. To date, SH3BP2 is the only gene identified to be responsible for cherubism. Since not all patients clinically diagnosed with cherubism had mutations in SH3BP2, we hypothesized that there may be novel cherubism genes and that these genes may play a role in jawbone homeostasis. Here, using whole exome sequencing, we identified homozygous loss-of-function variants in the opioid growth factor receptor like 1 (OGFRL1) gene in 2 independent autosomal recessive cherubism families from Syria and India. The newly identified pathogenic homozygous variants were not reported in any variant databases, suggesting that OGFRL1 is a novel gene responsible for cherubism. Single cell analysis of mouse jawbone tissue revealed that Ogfrl1 is highly expressed in myeloid lineage cells. We generated OGFRL1 knockout mice and mice carrying the Syrian frameshift mutation to understand the in vivo role of OGFRL1. However, neither mouse model recapitulated human cherubism or the phenotypes exhibited by SH3BP2 cherubism mice under physiological and periodontitis conditions. Unlike bone marrow-derived M-CSF-dependent macrophages (BMMs) carrying the SH3BP2 cherubism mutation, BMMs lacking OGFRL1 or carrying the Syrian mutation showed no difference in TNF-ɑ mRNA induction by LPS or TNF-ɑ compared to WT BMMs. Osteoclast formation induced by RANKL was also comparable. These results suggest that the loss-of-function effects of OGFRL1 in humans differ from those in mice and highlight the fact that mice are not always an ideal model for studying rare craniofacial bone disorders.
摘要：
Cherubism（OMIM118400）是儿童中一种罕见的颅面疾病，其特征是由于炎性纤维性病变的生长而导致的破坏性颌骨扩张。我们以前的研究表明，SH3结构域结合蛋白2（SH3BP2）中的功能获得突变是造成基差症的原因，而基差症的敲入小鼠模型可以概括基差症的特征，如破骨细胞形成增加和颌骨破坏。迄今为止,SH3BP2是唯一被鉴定为负责天使症的基因。由于并非所有临床诊断为天使症的患者都有SH3BP2突变，因此我们假设可能存在新的天使症基因，并且这些基因可能在颌骨稳态中起作用。这里,使用整个外显子组测序，我们在来自叙利亚和印度的2个独立的常染色体隐性遗传性小天使症家族中鉴定了阿片样生长因子受体样1(OGFRL1)基因的纯合功能缺失变异体.新发现的致病性纯合变体没有在任何变体数据库中报告，这表明OGFRL1是一个新的基因。小鼠颌骨组织的单细胞分析显示Ogfrl1在骨髓谱系细胞中高度表达。我们产生了OGFRL1敲除小鼠和携带叙利亚移码突变的小鼠，以了解OGFRL1的体内作用。然而,在生理和牙周炎条件下，小鼠模型或SH3BP2胆花症小鼠表现出的表型均未概括人类胆花症。不同于骨髓来源的M-CSF依赖性巨噬细胞（BMMs）携带SH3BP2胆识突变，缺乏OGFRL1或携带叙利亚突变的BMM与WTBMM相比，LPS或TNF-α诱导的TNF-αmRNA无差异。RANKL诱导的破骨细胞形成也具有可比性。这些结果表明，OGFRL1在人类中的功能丧失作用与小鼠中的作用不同，并强调了小鼠并不总是研究罕见颅面骨疾病的理想模型。
