Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Ann Neurol. 2011 Jun;69(6):1005-13. doi: 10.1002/ana.22338. Epub 2011 Mar 9.
Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogeneous muscular disease that presents with muscular dystrophy, joint contractures, and cardiomyopathy with conduction defects. Mutations in several nuclear envelope protein genes have been associated with EDMD in less than half of patients, implying the existence of other causative and modifier genes. We therefore analyzed TMEM43, which encodes LUMA, a newly identified nuclear membrane protein and also a binding partner of emerin and lamins, to investigate whether LUMA may contribute to the pathomechanism of EDMD-related myopathy.
Forty-one patients with EDMD-related myopathy were enrolled. In vitro and in vivo transfection analyses were performed to assay the binding partners and oligomerization of mutant LUMA.
We identified heterozygous missense mutations, p.Glu85Lys and p.Ile91Val in TMEM43, in 2 EDMD-related myopathy patients. Reduced nuclear staining of LUMA was observed in the muscle from the patient with p.Glu85Lys mutation. By in vitro transfection analysis, p.Glu85Lys mutant LUMA resulted to failure in oligomerization, a process that may be important for protein complex formation on nuclear membrane. Furthermore, we demonstrated for the first time that LUMA can interact with another nuclear membrane protein, SUN2, in addition to emerin. Cells expressing mutant LUMA revealed reduced nuclear staining with or without aggregates of emerin and SUN2 together with a higher proportion of abnormally shaped nuclei. In vivo expression of mutant LUMA by electroporation in mouse tibialis anterior muscles likewise demonstrated the decreased staining of emerin and SUN2 on myonuclei.
Our results suggest that mutant LUMAs may be associated with EDMD-related myopathy.
先天性肌营养不良症（EDMD）是一种遗传性异质性肌病，表现为肌营养不良、关节挛缩和伴有传导缺陷的心肌病。几种核包膜蛋白基因突变与不到一半的 EDMD 患者相关，这表明存在其他致病和修饰基因。因此，我们分析了编码 LUMA 的 TMEM43，LUMA 是一种新发现的核膜蛋白，也是 emerin 和 lamin 的结合伴侣，以研究 LUMA 是否可能导致 EDMD 相关肌病的发病机制。
纳入 41 例 EDMD 相关肌病患者。进行体外和体内转染分析，以检测突变 LUMA 的结合伴侣和寡聚化。
我们在 2 例 EDMD 相关肌病患者中发现了 TMEM43 的杂合错义突变 p.Glu85Lys 和 p.Ile91Val。在携带 p.Glu85Lys 突变的患者的肌肉中观察到 LUMA 的核染色减少。通过体外转染分析，p.Glu85Lys 突变 LUMA 导致寡聚化失败，这一过程可能对核膜上蛋白质复合物的形成很重要。此外，我们首次证明 LUMA 除了与 emerin 相互作用外，还可以与另一种核膜蛋白 SUN2 相互作用。表达突变 LUMA 的细胞显示出核内染色减少，与 emerin 和 SUN2 的聚集或不聚集，以及异常形状核的比例增加。通过电穿孔将突变 LUMA 在小鼠胫骨前肌中的体内表达同样表明，emerin 和 SUN2 在肌核上的染色减少。
我们的结果表明，突变 LUMA 可能与 EDMD 相关肌病有关。
