Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome
Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome
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DOI：
10.1136/jmg.2008.063693
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发表时间：
2009-03-01
影响因子：
4
通讯作者：
Wollmann, R. L.
中科院分区：
文献类型：
--
作者：
Maselli, R. A.;Ng, J. J.;Wollmann, R. L.
背景：我们描述了一种严重形式的先天性肌无力综合征（CMS），与先天性肾病和眼部畸形相关，由编码层粘连蛋白β 2亚基（LAMB2）的基因的两个截短突变引起。方法与结果：该患者对乙酰胆碱酯酶抑制治疗有严重不良反应史，对其进行突变分析，发现两种移框异等位基因突变，母体遗传1478delG，父系遗传4804delC。踝关节肌活检显示神经肌肉连接处的结构和功能严重扭曲，这与缺乏层粘连蛋白b2亚基的小鼠的情况惊人地相似。结果包括：轴突末端明显缩小，神经末梢被雪旺细胞包裹，原发性突触间隙严重扩大，突触间隙被雪旺细胞突侵袭，突触后褶皱适度简化，终板乙酰胆碱酯酶表达完整。终板电位量子含量明显降低，而微终板电位的频率和幅度仅略有降低，微终板电位衰减相位正常。肌、肾组织Western blot分析及肾组织免疫组化未见层粘连蛋白b2表达。结论：该病例代表了一种新型的突触性CMS，体现了与LAMB2突变相关的表型的广泛变异性，并强调了层粘连蛋白b2在人类神经肌肉连接发育中的基本作用。
Background: We describe a severe form of congenital myasthenic syndrome (CMS) associated with congenital nephrosis and ocular malformations caused by two truncating mutations in the gene encoding the laminin beta 2 subunit (LAMB2).Methods and results: Mutational analysis in the affected patient, who has a history of a serious untoward reaction to treatment with acetylcholinesterase inhibition, revealed two frame-shifting heteroallelic mutations, a maternally inherited 1478delG and a paternally inherited 4804delC. An anconeus muscle biopsy demonstrated a profound distortion of the architecture and function of the neuromuscular junction, which was strikingly similar to that seen in mice lacking laminin b2 subunit. The findings included: pronounced reduction of the axon terminal size with encasement of the nerve endings by Schwann cells, severe widening of the primary synaptic cleft and invasion of the synaptic space by the processes of Schwann cells, and moderate simplification of postsynaptic folds and intact expression of the endplate acetylcholinesterase. The endplate potential quantal content was notably reduced, while the frequencies and amplitudes of miniature endplate potentials were only moderately diminished and the decay phases of miniature endplate potentials were normal. Western blot analysis of muscle and kidney tissue and immunohistochemistry of kidney tissue showed no laminin b2 expression.Conclusion: This case, which represents a new type of synaptic CMS, exemplifies the wide variability of phenotypes associated with LAMB2 mutations and underscores the fundamental role that laminin b2 plays in the development of the human neuromuscular junction.