Mutations in the human TMEM16E/ANO5 gene are causative for gnathodiaphyseal dysplasia (GDD), a rare bone malformation and fragility disorder, and for two types of muscular dystrophy (MD). Previous studies have demonstrated that TMEM16E/ANO5 is a Ca2+ -activated phospholipid scramblase and that the mutation c.1538C>T (p.Thr513Ile) causing GDD leads to a gain-of-function phenotype. Here, using established HEK293-based functional assays, we investigated the effects of MD-related and further GDD-related amino acid exchanges on TMEM16E/ANO5 function in the same expression system. These experiments also revealed that the gradual changes in HEK293 cell morphology observed upon expression of TMEM16E/ANO5GDD mutants are a consequence of aberrant protein activity. Our results collectively demonstrate that, on the level of protein function, MD mutations are associated to loss-of-function and GDD mutations to gain-of-function phenotypes, confirming conjectures made on the basis of inheritance modes.

中文翻译：

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与骨发育不良或肌营养不良症相关的 TMEM16E/ANO5 突变对脂质扰乱产生相反的影响。

人类 TMEM16E/ANO5 基因的突变是导致颌骨发育不良 (GDD)（一种罕见的骨骼畸形和脆性障碍）以及两种类型的肌营养不良症 (MD) 的原因。先前的研究表明，TMEM16E/ANO5 是一种 Ca2+ 激活的磷脂扰乱酶，导致 GDD 的突变 c.1538C>T (p.Thr513Ile) 导致功能获得表型。在这里，我们使用已建立的基于 HEK293 的功能测定，研究了 MD 相关和进一步 GDD 相关氨基酸交换对同一表达系统中 TMEM16E/ANO5 功能的影响。这些实验还表明，在 TMEM16E/ANO5GDD 突变体表达后观察到的 HEK293 细胞形态的逐渐变化是异常蛋白质活性的结果。我们的结果共同表明，在蛋白质功能水平上，