Characterization of a Relatively Malignant Form of Osteopetrosis Caused by a Novel Mutation in the PLEKHM1 Gene
Characterization of a Relatively Malignant Form of Osteopetrosis Caused by a Novel Mutation in the PLEKHM1 Gene
复制标题
PLEKHM1 基因新突变引起的相对恶性骨石症的表征
DOI：
10.1002/jbmr.2885
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发表时间：
2016-11-01
影响因子：
6.2
通讯作者：
Xu, Chao
中科院分区：
文献类型：
--
作者：
Bo, Tao;Yan, Fang;Xu, Chao
骨化症(OMIM：611497)，字面意思是“石骨”，是一组遗传性骨骼疾病，其特征是由于破骨细胞功能缺陷而导致骨量增加。1例患者报告有频繁骨折、虚弱和疲劳的病史，于2011年住进该院。患者出现典型的骨化病特征：轻微创伤后骨折，早期牙齿脱落，贫血，肝脾肿大，骨密度(BMD)普遍增加。除了父亲抱怨牙齿过度脱落外，他的母亲、两个姐妹、儿子和女儿都很健康。家庭成员的血液样本被抽取进行基因分析。对含有Pleckstrin同源结构域的家族M(含Run结构域)成员1(PLEKHM1)基因的整个编码区和邻近的剪接点进行了测序。在患者的亲属中未发现外显子11杂合性缺失突变(c.3051_3052delCA)。该突变导致翻译产物具有高度受损的Rubcon同源结构域。用HEK293细胞进行的免疫共沉淀和免疫荧光分析表明，与野生型PLEKHM1相比，PLEKHM1 CA缺失突变体的过表达导致PLEKHM1与小GTP酶Rab7之间的相互作用显著减少。在表达突变的HEK293和U937细胞中，正常的吞噬和自噬过程被扰乱，分别表现为表皮生长因子受体(EGFR)的降解和LC3-I/II比率的改变，这可能导致破骨细胞功能的缺陷。对患者的四年随访研究表明，PLEKHM1依赖型骨化病相对恶性，有明显的全血细胞减少和肝脾肿大的症状。(C)2016年美国骨与矿物研究学会。
Osteopetrosis (OMIM: 611497), literally "stone bone," is a group of inherited bone disorders characterized by increased skeletal mass due to defective osteoclast function. A patient who reported a history of frequent fractures, weakness and fatigue was admitted to our hospital in 2011. The patient presented with the typical features of osteopetrosis: fractures after minor trauma, early tooth loss, anemia, hepatosplenomegaly, and a generalized increase in bone mineral density (BMD). Aside from his father's complaint of excessive tooth loss, his mother, two sisters, son, and daughter were healthy. Blood samples of the family members were drawn for genetic analyses. The entire coding region and adjacent splice sites of the pleckstrin homology domain-containing family M (with RUN domain) member 1 (PLEKHM1) gene were sequenced. One mutation, a heterozygous deletion mutation in exon 11 (c.3051_3052delCA), was identified in the patient but not in his relatives. The mutation leads to a translation product with a highly impaired Rubicon homology domain. Co-immunoprecipitation and immunofluorescence analyses using HEK293 cells showed that overexpression of a PLEKHM1 CA-deletion mutant resulted in a dramatic decrease in the interaction between PLEKHM1 and the small GTPase Rab7 compared to wild-type PLEKHM1. The normal processes of endocytosis and autophagy were disturbed in cells expressing the mutant (transfected HEK293 and U937 cells), as indicated by epidermal growth factor receptor (EGFR) degradation and an altered LC3-I/II ratio, respectively, which may lead to a defect in osteoclast function. A four-year follow-up study of the patient showed that the PLEKHM1-dependent osteopetrosis was relatively malignant, with significant symptoms of pancytopenia and hepatosplenomegaly. (C) 2016 American Society for Bone and Mineral Research.