TMEM16E/ANO5 mutations related to bone dysplasia or muscular dystrophy cause opposite effects on lipid scrambling
TMEM16E/ANO5 mutations related to bone dysplasia or muscular dystrophy cause opposite effects on lipid scrambling
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DOI：
10.1002/humu.24006
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发表时间：
2020-03-18
期刊：
影响因子：
3.9
通讯作者：
Boccaccio, Anna
中科院分区：
文献类型：
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作者：
Di Zanni, Eleonora;Gradogna, Antonella;Boccaccio, Anna
人类 TMEM16E/ANO5 基因突变是导致颌骨干发育不良 (GDD)（一种罕见的骨畸形和脆性障碍）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，并且引起 GDD 的突变 c.1538C>T (p.Thr513Ile) 会导致功能获得表型。在这里，使用已建立的基于 HEK293 的功能测定，我们研究了 MD 相关和进一步 GDD 相关的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，TMEM16E/ANO5(GDD) 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活性的结果。我们的结果共同证明，在蛋白质功能水平上，MD 突变与功能丧失相关，GDD 突变与功能获得表型相关，证实了基于遗传模式的猜想。
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/ANO5(GDD) 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.