Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission.
Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission.
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LAMA5 纯合序列变异导致突触前先天性肌无力综合征，伴有近视、面部抽搐和神经肌肉传递障碍。
DOI：
10.1002/ajmg.a.38291
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
McDonald,CraigM
中科院分区：
文献类型：
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作者：
Maselli,RicardoA;Arredondo,Juan;Vázquez,Jessica;Chong,JessicaX;UniversityofWashingtonCenterforMendelianGenomics;Bamshad,MichaelJ;Nickerson,DeborahA;Lara,Marian;Ng,Fiona;Lo,VictoriaL;Pytel,Peter;McDonald,CraigM
编码层粘连蛋白α亚基亚型的基因缺陷与各种表型表现有关，包括脑畸形、肌营养不良、眼缺陷、心肌病和皮肤异常。我们在此报告了一个层粘连蛋白α 5亚基基因（LAMA 5）纯合变异的近亲患者的神经肌肉传递严重缺陷。变异体c.8046C>T（p.Arg2659Trp）是罕见的，并且具有预测的有害作用。受影响的个人，谁也携带一种罕见的纯合序列变异在LAMA 1，有肌肉无力，近视，面部抽搐。脑磁共振成像显示轻度容量损失和脑室周围T2延长。重复神经刺激显示运动后即刻复合肌肉动作电位振幅下降50%，易化250%。终板研究发现终板电位量子含量显著减少，终板具有正常的突触后折叠，被小神经末梢剥脱或部分占据。表达研究表明，p.Arg2659Trp导致层粘连蛋白α-5与SV 2A的结合减少，并损害了原代神经元培养物中层粘连蛋白-521细胞粘附和细胞投射支持。总之，本报告描述了aLAMA 5突变患者的严重神经肌肉传递障碍，扩展了与编码α层粘连蛋白的基因缺陷相关的表型列表。
Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha‐5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant inLAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha‐5 to SV2A and impaired laminin‐521 cell‐adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with aLAMA5mutation expands the list of phenotypes associated with defects in genes encoding alpha‐laminins.