NOVEL MUTATIONS IN THE WNT1, TMEM38B, P4HB, AND PLS3 GENES IN FOUR UNRELATED CHINESE FAMILIES WITH OSTEOGENESIS IMPERFECTA
NOVEL MUTATIONS IN THE WNT1, TMEM38B, P4HB, AND PLS3 GENES IN FOUR UNRELATED CHINESE FAMILIES WITH OSTEOGENESIS IMPERFECTA
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四个不相关的中国成骨不全家系中 WNT1、TMEM38B、P4HB 和 PLS3 基因的新突变
DOI：
10.4158/ep-2018-0443
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发表时间：
2019-03-01
影响因子：
4.2
通讯作者：
Zhang, Zhen-Lin
中科院分区：
文献类型：
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作者：
Cao, Yang-Jia;Zhang, Hao;Zhang, Zhen-Lin
目的：成骨不全症（OI）是一组遗传性脆性骨疾病，大多数是由COL1A1和COL1A2基因的致病性变异引起。我们试图确定没有 COL1A1 或 COL1A2 突变的中国患者成骨不全的遗传原因和表型。方法：招募了 23 名被诊断为散发性成骨不全但不携带 COL1A1/2 突变的患者，并使用罕见成骨不全相关基因的新一代靶向测序技术对他们的基因组 DNA 进行了分析。使用桑格测序验证了先证者及其父母所产生的破坏性突变。此外，在先证者1中评估了长期双膦酸盐治疗的疗效。结果：分别在先证者1和先证者2中鉴定出WNT1和TMEM38B基因的复合杂合变异。先证者3中鉴定出P4HB基因杂合突变，先证者4中鉴定出PLS3半合突变。WNT1、TMEM38B和PLS3基因突变的先证者的未患病父母（先证者4的父亲除外）分别是每种变异的杂合携带者。值得注意的是，先证者 3 具有特征性的眼球突出、扁平鼻梁和扁平宽额头。没有患者出现牙本质发育不全或听力损失。此外，双磷酸盐对携带 WNT1 突变的先证者 1 产生了有益的影响，通过增加骨矿物质密度 Z 值、重塑受压椎骨并降低骨折风险。结论：我们鉴定了新的突变，并扩大了极其罕见的成骨不全症的表型和基因型谱。
Objective: Osteogenesis imperfecta (OI) is a group of heritable fragile bone diseases, and the majority are caused by pathogenic variants in the COL1A1 and COL1A2 genes. We sought to identify the genetic causes and phenotypes of OI in Chinese patients without COL1A1 or COL1A2 mutations.Methods: Twenty-three patients who were diagnosed with sporadic OI but did not carry COL1A1/2 mutations were recruited, and their genomic DNA was analyzed using targeted next-generation sequencing of rare OI-related genes. The resulting damaging mutations in the probands and their parents were verified using Sanger sequencing. Moreover, the efficacy of long-term bisphosphonate treatment was evaluated in proband 1.Results: Compound heterozygous variants in the WNT1 and TMEM38B genes were identified in proband 1 and proband 2, respectively. A heterozygous mutation in the P4HB gene was identified in proband 3, and a hemizygous mutation in PLS3 was identified in proband 4. The unaffected parents of the probands (except the father of proband 4) with mutations in the WNT1, TMEM38B, and PLS3 genes were heterozygous carriers of each of the variants, respectively. Notably, proband 3 had the characteristic exophthalmos, flat nasal bridge and flat, wide forehead. None of the patients presented with dentinogenesis imperfecta or hearing loss. Furthermore, bisphosphonates exerted beneficial effects on proband 1, who carried the WNT1 mutations, by increasing bone mineral density Z-score, reshaping the compressed vertebrae and decreasing the fracture risk.Conclusion: We identified novel mutations and expanded the spectrum of phenotypes and genotypes of the extremely rare disorder OI.