Autosomal recessive mutations in Anoctamin 5 (ANO5/TMEM16E), a member of the transmembrane 16 (TMEM16) family of Ca2+-activated ion channels and phospholipid scramblases, cause adult-onset muscular dystrophies (limb girdle muscular dystrophy 2L (LGMD2L) and Miyoshi Muscular Dystrophy (MMD3). However, the molecular role of ANO5 is unclear and ANO5 knockout mouse models show conflicting requirements of ANO5 in muscle. To study the role of ANO5 in human muscle cells we generated a myoblast line from a MMD3-patient carrying the c.2272C>T mutation, which we find causes the mutant protein to be degraded. The patient myoblasts exhibit normal myogenesis, but are compromised in their plasma membrane repair (PMR) ability. The repair deficit is linked to the poor ability of the endoplasmic reticulum (ER) to clear cytosolic Ca2+ increase caused by focal plasma membrane injury. Expression of wild-type ANO5 or pharmacological prevention of injury-triggered cytosolic Ca2+ overload enable injured patient muscle cells to repair. A homology model of ANO5 shows that several of the known LGMD2L/MMD3 patient mutations line the transmembrane region of the protein implicated in its channel activity. These results point to a role of cytosolic Ca2+ homeostasis in PMR, indicate a role for ANO5 in ER-mediated cytosolic Ca2+ uptake and identify normalization of cytosolic Ca2+ homeostasis as a potential therapeutic approach to treat muscular dystrophies caused by ANO5 deficit.

中文翻译：

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钙稳态失调会阻止Anoctamin 5 / TMEM16E缺乏的患者肌肉细胞中的质膜修复。

修复缺陷与内质网（ER）清除由局灶性质膜损伤引起的胞质Ca2 +增加的能力差有关。野生型ANO5的表达或损伤触发的胞质Ca2 +超载的药理预防使得受伤的患者肌肉细胞得以修复。ANO5的同源性模型显示，一些已知的LGMD2L / MMD3患者突变位于该蛋白的跨膜区中，这与该蛋白的通道活性有关。这些结果表明胞质Ca2 +稳态在PMR中的作用，表明ANO5在ER介导的胞质Ca2 +摄取中的作用，并确定胞质Ca2 +稳态的正常化是治疗由ANO5缺乏引起的肌营养不良的潜在治疗方法。野生型ANO5的表达或损伤触发的胞质Ca2 +超载的药理预防使得受伤的患者肌肉细胞得以修复。ANO5的同源性模型显示，一些已知的LGMD2L / MMD3患者突变位于该蛋白的跨膜区中，这与该蛋白的通道活性有关。这些结果表明胞质Ca2 +稳态在PMR中的作用，表明ANO5在ER介导的胞质Ca2 +摄取中的作用，并确定胞质Ca2 +稳态的正常化是治疗由ANO5缺乏引起的肌营养不良的潜在治疗方法。野生型ANO5的表达或损伤触发的胞质Ca2 +超载的药理预防使得受伤的患者肌肉细胞得以修复。ANO5的同源性模型显示，一些已知的LGMD2L / MMD3患者突变位于该蛋白的跨膜区中，这与该蛋白的通道活性有关。这些结果表明胞质Ca2 +稳态在PMR中的作用，表明ANO5在ER介导的胞质Ca2 +摄取中的作用，并确定胞质Ca2 +稳态的正常化是治疗由ANO5缺乏引起的肌营养不良的潜在治疗方法。