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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint-waddler mice
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Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint-waddler mice

机译：粘蛋白瞬时受体电位通道中的激活突变导致varitint-waddler小鼠黑素细胞损失

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摘要

Transient receptor potential (TRP) genes of the mucolipin subfamily (TRPML1-3 and MCOLN1-3) are presumed to encode ion channel proteins of intracellular endosomes and lysosomes. Mutations in human TRPML1 (mucolipin 1/MCOLN1) result in mucolipidosis type IV, a severe inherited neurodegenerative disease associated with defective lysosomal biogenesis and trafficking. A mutation in mouse TRPML3 (A419P; TRPML3~(Va)) results in the varitint-waddler (Va) phenotype. Va mice are deaf, exhibit circling behavior due to vestibular defects, and have variegated/dilute coat color as a result of pigmentation defects. Prior electrophysiological studies of presumed TRPML plasma membrane channels are contradictory and inconsistent with known TRP channel properties. Here, we report that the Va mutation produces a gain-of-function that allows TRPML1 and TRPML3 to be measured and identified as inwardly rectifying, proton-impermeant, Ca~(2+)-permeant cation channels. TRPML3 is highly expressed in normal melanocytes. Melanocyte markers are lost in the Va mouse, suggesting that their variegated and hypopigmented fur is caused by severe alteration of melanocyte function or cell death. TRPML3~(Va) expression in melanocyte cell lines results in high resting Ca~(2+) levels, rounded, poorly adherent cells, and loss of membrane integrity. We conclude that the Va phenotype is caused by mutation-induced TRPML3 gain-of-function, resulting in cell death.
机译：推测粘蛋白亚家族的瞬时受体电位（TRP）基因（TRPML1-3和MCOLN1-3）编码细胞内内体和溶酶体的离子通道蛋白。人TRPML1（粘蛋白1 / MCOLN1）中的突变导致粘液脂质型IV，这是一种严重的遗传性神经退行性疾病，与溶酶体的生物发生和运输缺陷有关。小鼠TRPML3（A419P; TRPML3〜（Va））的突变导致了varitint-waddler（Va）表型。 Va小鼠是聋的，由于前庭缺损而表现出盘旋行为，并且由于色素沉着缺陷而具有杂色/稀薄的外套颜色。先前对TRPML质膜通道的电生理研究是矛盾的，并且与已知的TRP通道特性不一致。在这里，我们报告说，Va突变产生了一个功能增益，该功能增益允许测量TRPML1和TRPML3并将其识别为向内整流，不渗透质子，Ca〜（2+）的阳离子通道。 TRPML3在正常黑素细胞中高表达。黑素细胞标记在Va小鼠中丢失，表明它们的杂色和色素沉着的皮毛是由黑素细胞功能的严重改变或细胞死亡引起的。黑色素细胞细胞系中TRPML3〜（Va）的表达导致高的静息Ca〜（2+）水平，圆形，贴壁不良的细胞以及膜完整性的丧失。我们得出结论，Va表型是由突变诱导的TRPML3功能获得引起的，从而导致细胞死亡。

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