Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta
Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta
复制标题
DOI：
10.1016/j.ajhg.2019.08.008
复制
发表时间：
2019-10-03
影响因子：
9.8
通讯作者：
Netzer, Christian
中科院分区：
文献类型：
--
作者：
Moosa, Shahida;Yamamoto, Guilherme L.;Netzer, Christian
成骨不全（OI）包括一组遗传异质性骨骼脆性疾病。在这里，我们报告了五个独立的家庭进行性变形类型的OI，其中我们确定了四个纯合截断或移码突变的MESD。受影响的个人有复发性骨折，至少有一个有少牙。MESD编码典型无翅相关整合位点（WNT）信号受体LRP 5和LRP 6的内质网（ER）伴侣蛋白。由于完全缺乏MESD导致小鼠胚胎死亡，我们假设OI相关突变是亚型等位基因，因为这些突变发生在伴侣活性结构域的下游，但ER保留结构域的上游。这将分别与LRP 5和LRP 6缺陷的人的骨骼脆弱性和少牙症的临床表型一致。当我们在HEK293T细胞中表达野生型（WT）和突变型MESD时，我们在细胞裂解物中检测到WT MESD，但在条件培养基中检测不到，而突变型MESD则匡威。我们观察到WT和突变体MESD都保留了分子伴侣LRP 5的能力。因此，01相关的MESD突变产生亚纯型等位基因，其未能保持在ER内显著减少但不完全消除LRP 5和LRP 6运输。由于这些个体没有眼睛异常（发生在完全缺乏LRP 5的个体中），并且既没有肢体也没有大脑图案缺陷（这两者都发生在完全缺乏LRP 6的小鼠中），我们推断骨量增加和牙齿图案对减少的典型WNT信号传导比其他发育过程更敏感。可以增加LRP5和LRP6介导的WNT信号传导的生物制剂可以使MESD相关的OI患者受益。
Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, 01-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.